Genetic Variant DCHS2:p.Ser2758Asn (chr4-154236379-C-T) – 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.8273G>A(p.Ser2758Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00785 in 1,614,012 control chromosomes in the GnomAD database, including 778 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.040 ( 392 hom., cov: 33)

Exomes 𝑓: 0.0045 ( 386 hom. )

Consequence

DCHS2
NM_001358235.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -1.42

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=0.002483964).

BP6

Variant 4-154236379-C-T is Benign according to our data. Variant chr4-154236379-C-T is described in ClinVar as [Benign]. Clinvar id is 3055607.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
DCHS2	NM_001358235.2 link	c.8273G>A	p.Ser2758Asn	missense_variant	Exon 20 of 20	ENST00000357232.10	NP_001345164.1
LOC101927947	XR_007058335.1 link	n.689+29326C>T		intron_variant	Intron 5 of 5
LOC101927947	XR_007058336.1 link	n.4255+29326C>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.8273G>A	p.Ser2758Asn	missense_variant	Exon 20 of 20	1	NM_001358235.2	ENSP00000349768.5		Q6V1P9-1

Frequencies

GnomAD3 genomes

AF:

0.0396

AC:

6026

AN:

152142

Hom.:

391

Cov.:

show subpopulations

Gnomad AFR

AF:

0.136

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0182

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.0330

GnomAD3 exomes

AF:

0.0105

AC:

2642

AN:

250748

Hom.:

161

AF XY:

0.00779

AC XY:

1056

AN XY:

135536

show subpopulations

Gnomad AFR exome

AF:

0.136

Gnomad AMR exome

AF:

0.00726

Gnomad ASJ exome

AF:

0.00467

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000804

Gnomad OTH exome

AF:

0.00442

GnomAD4 exome

AF:

0.00454

AC:

6637

AN:

1461752

Hom.:

386

Cov.:

AF XY:

0.00406

AC XY:

2950

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.147

Gnomad4 AMR exome

AF:

0.00812

Gnomad4 ASJ exome

AF:

0.00333

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000527

Gnomad4 OTH exome

AF:

0.0101

GnomAD4 genome

AF:

0.0397

AC:

6041

AN:

152260

Hom.:

392

Cov.:

AF XY:

0.0384

AC XY:

2856

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.136

Gnomad4 AMR

AF:

0.0182

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000750

Gnomad4 OTH

AF:

0.0326

Alfa

AF:

0.00652

Hom.:

Bravo

AF:

0.0454

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.130

AC:

574

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.0128

AC:

1549

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.00131

EpiControl

AF:

0.00113

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

0.072

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.0050

DANN

Benign

0.20

Eigen

Benign

-2.5

Eigen_PC

Benign

-2.5

FATHMM_MKL

Benign

0.027

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.30

REVEL

Benign

0.12

MPC

0.070

ClinPred

0.0077

GERP RS

-12

gMVP

0.030

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