rs2302787

chr3-9938029-C-Gchr3-9938029-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.51

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 ClinVar 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 Lovd as [Benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 302 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRELD1	NM_001077415.3	c.383C>G	p.Pro128Arg	missense_variant	5/11	ENST00000452070.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRELD1	ENST00000452070.6	c.383C>G	p.Pro128Arg	missense_variant	5/11	2	NM_001077415.3	P1

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 302 AN: 152158 Hom.: 3 Cov.: 31

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

GnomAD3 exomes AF: 0.00448 AC: 1123 AN: 250454 Hom.: 23 AF XY: 0.00428 AC XY: 580 AN XY: 135616

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 SAS exome AF: 0.00147

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.: 41 Cov.: 31 AF XY: 0.00154 AC XY: 1118 AN XY: 727004

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.0452

Gnomad4 SAS exome AF: 0.00186

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000549

Gnomad4 OTH exome AF: 0.00326

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152276 Hom.: 3 Cov.: 31 AF XY: 0.00244 AC XY: 182 AN XY: 74468

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.0502

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.00209

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00409 AC: 496

Asia WGS AF: 0.0270 AC: 95 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Atrioventricular septal defect, susceptibility to, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2023

- -

CRELD1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2024

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	29
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	D
MetaRNN	Benign	0.0099	T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.8	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.58	T
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	T
GERP RS		5.2
Varity_R		0.64
gMVP		0.88

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

LitVar

Other links and lift over

dbSNP: rs2302787; hg19: chr3-9979713;