dbSNP rs2125328927: CRELD1:p.Cys46Ser (chr3-9934574-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001077415.3(CRELD1):c.136T>A(p.Cys46Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C46G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CRELD1
NM_001077415.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.44

Publications

0 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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.784

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRELD1	NM_001077415.3 link	c.136T>A	p.Cys46Ser	missense_variant	Exon 2 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.136T>A	p.Cys46Ser	missense_variant	Exon 2 of 11	2	NM_001077415.3	ENSP00000393643.2		Q96HD1-1
ENSG00000288550	ENST00000683484.1 link	n.1400-261T>A		intron_variant	Intron 16 of 23			ENSP00000507040.1		A0A804HIF2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461756

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727166

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111942

Other (OTH)

AF:

0.00

AC:

AN:

60386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

T;T;T;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.76

.;.;T;T

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.78

D;D;D;D

MetaSVM

Uncertain

0.32

MutationAssessor

Uncertain

2.5

M;M;M;M

PhyloP100

4.4

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-6.3

D;D;D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Uncertain

0.031

D;D;D;D

Polyphen

0.98

D;D;D;D

Vest4

0.80

MutPred

0.42

Loss of glycosylation at P41 (P = 0.0038);Loss of glycosylation at P41 (P = 0.0038);Loss of glycosylation at P41 (P = 0.0038);Loss of glycosylation at P41 (P = 0.0038);

MVP

0.91

MPC

0.72

ClinPred

0.98

GERP RS

4.2

PromoterAI

0.0097

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.68

gMVP

0.94

Mutation Taster

=48/52

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs2125328927

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over