Genetic Variant DCHS2:p.Gly2615Ser (chr4-154236809-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001358235.2(DCHS2):c.7843G>A(p.Gly2615Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00173 in 1,613,958 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0092 ( 25 hom., cov: 33)

Exomes 𝑓: 0.00095 ( 20 hom. )

Consequence

DCHS2
NM_001358235.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 4.76

Variant links:

Genes affected

DCHS2 (HGNC:23111): (dachsous cadherin-related 2) This gene encodes a large protein that contains many cadherin domains and likely functions in cell adhesion. Genome-wide association studies suggest that this gene may be important in Alzheimer's disease, compressive strength index, and appendicular lean mass. [provided by RefSeq, May 2017]

DCHS2 links:

ENSG00000278981 (HGNC:):

ENSG00000278981 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0061916113).

BP6

Variant 4-154236809-C-T is Benign according to our data. Variant chr4-154236809-C-T is described in ClinVar as [Benign]. Clinvar id is 3039356.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00921 (1402/152266) while in subpopulation AFR AF= 0.032 (1328/41542). AF 95% confidence interval is 0.0305. There are 25 homozygotes in gnomad4. There are 664 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
DCHS2	NM_001358235.2 link	c.7843G>A	p.Gly2615Ser	missense_variant	Exon 20 of 20	ENST00000357232.10	NP_001345164.1
LOC101927947	XR_007058335.1 link	n.689+29756C>T		intron_variant	Intron 5 of 5
LOC101927947	XR_007058336.1 link	n.4255+29756C>T		intron_variant	Intron 12 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCHS2	ENST00000357232.10 link	c.7843G>A	p.Gly2615Ser	missense_variant	Exon 20 of 20	1	NM_001358235.2	ENSP00000349768.5		Q6V1P9-1

Frequencies

GnomAD3 genomes

AF:

0.00920

AC:

1400

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0320

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00717

GnomAD3 exomes

AF:

0.00231

AC:

578

AN:

250334

Hom.:

AF XY:

0.00177

AC XY:

239

AN XY:

135276

show subpopulations

Gnomad AFR exome

AF:

0.0300

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000239

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.000948

AC:

1386

AN:

1461692

Hom.:

Cov.:

AF XY:

0.000825

AC XY:

600

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.0318

Gnomad4 AMR exome

AF:

0.00159

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000106

Gnomad4 OTH exome

AF:

0.00197

GnomAD4 genome

AF:

0.00921

AC:

1402

AN:

152266

Hom.:

Cov.:

AF XY:

0.00892

AC XY:

664

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0320

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00213

Hom.:

Bravo

AF:

0.0103

ESP6500AA

AF:

0.0275

AC:

121

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00292

AC:

354

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

DCHS2-related disorder

Benign:1

Mar 14, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

MetaRNN

Benign

0.0062

MetaSVM

Uncertain

-0.0092

PrimateAI

Benign

0.41

REVEL

Uncertain

0.47

MPC

0.41

ClinPred

0.11

GERP RS

6.0

gMVP

0.51

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