Genetic Variant DCHS1:p.Arg2513His (chr11-6624138-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS1

The NM_003737.4(DCHS1):c.7538G>A(p.Arg2513His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000245 in 1,611,506 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2513C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

DCHS1
NM_003737.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter P:1B:1

Conservation

PhyloP100: 2.76

Variant links:

Genes affected

DCHS1 (HGNC:13681): (dachsous cadherin-related 1) This gene is a member of the cadherin superfamily whose members encode calcium-dependent cell-cell adhesion molecules. The encoded protein has a signal peptide, 27 cadherin repeat domains and a unique cytoplasmic region. This particular cadherin family member is expressed in fibroblasts but not in melanocytes or keratinocytes. The cell-cell adhesion of fibroblasts is thought to be necessary for wound healing. [provided by RefSeq, Jul 2008]

DCHS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03747222).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000171 (26/152382) while in subpopulation EAS AF= 0.00386 (20/5188). AF 95% confidence interval is 0.00255. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCHS1	NM_003737.4 link	c.7538G>A	p.Arg2513His	missense_variant	Exon 21 of 21	ENST00000299441.5	NP_003728.1	Q96JQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCHS1	ENST00000299441.5 link	c.7538G>A	p.Arg2513His	missense_variant	Exon 21 of 21	1	NM_003737.4	ENSP00000299441.3		Q96JQ0

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00385

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000420

AC:

103

AN:

245034

Hom.:

AF XY:

0.000414

AC XY:

AN XY:

132978

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00307

Gnomad SAS exome

AF:

0.000924

Gnomad FIN exome

AF:

0.0000472

Gnomad NFE exome

AF:

0.000154

Gnomad OTH exome

AF:

0.000334

GnomAD4 exome

AF:

0.000253

AC:

369

AN:

1459124

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

215

AN XY:

725776

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00328

Gnomad4 SAS exome

AF:

0.000837

Gnomad4 FIN exome

AF:

0.000247

Gnomad4 NFE exome

AF:

0.000116

Gnomad4 OTH exome

AF:

0.000398

GnomAD4 genome

AF:

0.000171

AC:

AN:

152382

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00386

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000867

Hom.:

Bravo

AF:

0.000193

ExAC

AF:

0.000486

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Mitral valve prolapse, myxomatous 2

Pathogenic:1

Sep 03, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Benign:1

Dec 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.092

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.014

MetaRNN

Benign

0.037

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.65

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.3

REVEL

Benign

0.18

Sift

Uncertain

0.013

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.84

MVP

0.58

MPC

0.84

ClinPred

0.046

GERP RS

4.8

Varity_R

0.060

gMVP

0.28

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over