Genetic Variant DCHS2:p.Asn2977His (chr4-154235723-T-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001358235.2(DCHS2):c.8929A>C(p.Asn2977His) variant causes a missense change. The variant allele was found at a frequency of 0.0076 in 1,613,842 control chromosomes in the GnomAD database, including 691 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.039 ( 370 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 321 hom. )

Consequence

DCHS2
NM_001358235.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 4.21

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:

ENSG00000280241 (HGNC:):

ENSG00000280241 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018635988).

BP6

Variant 4-154235723-T-G is Benign according to our data. Variant chr4-154235723-T-G is described in ClinVar as [Benign]. Clinvar id is 3055622.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
DCHS2	NM_001358235.2 link	c.8929A>C	p.Asn2977His	missense_variant	Exon 20 of 20	ENST00000357232.10	NP_001345164.1
LOC101927947	XR_007058335.1 link	n.689+28670T>G		intron_variant	Intron 5 of 5
LOC101927947	XR_007058336.1 link	n.4255+28670T>G		intron_variant	Intron 12 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCHS2	ENST00000357232.10 link	c.8929A>C	p.Asn2977His	missense_variant	Exon 20 of 20	1	NM_001358235.2	ENSP00000349768.5		Q6V1P9-1

Frequencies

GnomAD3 genomes

AF:

0.0394

AC:

5996

AN:

152082

Hom.:

371

Cov.:

show subpopulations

Gnomad AFR

AF:

0.135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0157

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0255

Gnomad NFE

AF:

0.000970

Gnomad OTH

AF:

0.0417

GnomAD3 exomes

AF:

0.0106

AC:

2668

AN:

250840

Hom.:

143

AF XY:

0.00801

AC XY:

1086

AN XY:

135548

show subpopulations

Gnomad AFR exome

AF:

0.137

Gnomad AMR exome

AF:

0.00726

Gnomad ASJ exome

AF:

0.00437

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000900

Gnomad OTH exome

AF:

0.00605

GnomAD4 exome

AF:

0.00428

AC:

6254

AN:

1461642

Hom.:

321

Cov.:

AF XY:

0.00382

AC XY:

2776

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.135

Gnomad4 AMR exome

AF:

0.00778

Gnomad4 ASJ exome

AF:

0.00394

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000559

Gnomad4 OTH exome

AF:

0.00924

GnomAD4 genome

AF:

0.0394

AC:

6004

AN:

152200

Hom.:

370

Cov.:

AF XY:

0.0371

AC XY:

2764

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.134

Gnomad4 AMR

AF:

0.0156

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000624

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000971

Gnomad4 OTH

AF:

0.0417

Alfa

AF:

0.00281

Hom.:

Bravo

AF:

0.0450

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.129

AC:

567

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.0131

AC:

1589

Asia WGS

AF:

0.00693

AC:

AN:

3476

EpiCase

AF:

0.00125

EpiControl

AF:

0.00154

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

DCHS2-related disorder

Benign:1

Mar 03, 2020

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

0.21

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.50

REVEL

Uncertain

0.31

MPC

0.43

ClinPred

0.012

GERP RS

5.7

gMVP

0.19

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