3-9938029-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001077415.3(CRELD1):c.383C>G(p.Pro128Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,613,702 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0015 ( 41 hom. )

Consequence

CRELD1
NM_001077415.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.51

Publications

10 publications found

Variant links:

Genes affected

CRELD1 (HGNC:14630): (cysteine rich with EGF like domains 1) This gene encodes a member of a subfamily of epidermal growth factor-related proteins. The encoded protein is characterized by a cysteine-rich with epidermal growth factor-like domain. This protein may function as a cell adhesion molecule. Mutations in this gene are the cause of atrioventricular septal defect. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]

CRELD1 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
atrioventricular septal defect, susceptibility to, 2
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
Jeffries-Lakhani neurodevelopmental syndrome
Inheritance: AR Classification: MODERATE Submitted by: G2P
congenital heart disease
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

CRELD1 links:

ENSG00000288550 (HGNC:):

ENSG00000288550 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009946257).

BP6

Variant 3-9938029-C-G is Benign according to our data. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9938029-C-G is described in CliVar as Benign. Clinvar id is 238217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00198 (301/152276) while in subpopulation EAS AF = 0.0502 (260/5180). AF 95% confidence interval is 0.0452. There are 3 homozygotes in GnomAd4. There are 182 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRELD1	NM_001077415.3 link	c.383C>G	p.Pro128Arg	missense_variant	Exon 5 of 11	ENST00000452070.6	NP_001070883.2	Q96HD1-1A0A024R2G1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRELD1	ENST00000452070.6 link	c.383C>G	p.Pro128Arg	missense_variant	Exon 5 of 11	2	NM_001077415.3	ENSP00000393643.2		Q96HD1-1
ENSG00000288550	ENST00000683484.1 link	n.*108+357C>G		intron_variant	Intron 18 of 23			ENSP00000507040.1		A0A804HIF2

Frequencies

GnomAD3 genomes

AF:

0.00198

AC:

302

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.0503

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00448

AC:

1123

AN:

250454

AF XY:

0.00428

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.000597

Gnomad EAS exome

AF:

0.0567

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000707

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00153

AC:

2236

AN:

1461426

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

1118

AN XY:

727004

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33468

American (AMR)

AF:

0.000112

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000459

AC:

AN:

26134

East Asian (EAS)

AF:

0.0452

AC:

1793

AN:

39698

South Asian (SAS)

AF:

0.00186

AC:

160

AN:

86222

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53314

Middle Eastern (MID)

AF:

0.000178

AC:

AN:

5610

European-Non Finnish (NFE)

AF:

0.0000549

AC:

AN:

1111904

Other (OTH)

AF:

0.00326

AC:

197

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

120

240

361

481

601

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00198

AC:

301

AN:

152276

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

182

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41550

American (AMR)

AF:

0.000392

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.0502

AC:

260

AN:

5180

South Asian (SAS)

AF:

0.00290

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68020

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000218

Hom.:

Bravo

AF:

0.00209

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00409

AC:

496

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Atrioventricular septal defect, susceptibility to, 2

Benign:1

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CRELD1-related disorder

Benign:1

Feb 22, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;T;T;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

.;.;D;D

MetaRNN

Benign

0.0099

T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.8

M;M;M;M

PhyloP100

7.5

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-8.6

D;D;D;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.013

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.89

MVP

0.56

MPC

0.69

ClinPred

0.14

GERP RS

5.2

Varity_R

0.64

gMVP

0.88

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over