Genetic Variant DCHS2:p.Pro2800Pro (chr4-154236252-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001358235.2(DCHS2):c.8400G>A(p.Pro2800Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,613,936 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0067 ( 10 hom., cov: 32)

Exomes 𝑓: 0.00079 ( 14 hom. )

Consequence

DCHS2
NM_001358235.2 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.0530

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 4-154236252-C-T is Benign according to our data. Variant chr4-154236252-C-T is described in ClinVar as [Benign]. Clinvar id is 3041244.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-0.053 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00673 (1024/152216) while in subpopulation AFR AF= 0.0236 (979/41540). AF 95% confidence interval is 0.0223. There are 10 homozygotes in gnomad4. There are 488 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
DCHS2	NM_001358235.2 link	c.8400G>A	p.Pro2800Pro	synonymous_variant	Exon 20 of 20	ENST00000357232.10	NP_001345164.1
LOC101927947	XR_007058335.1 link	n.689+29199C>T		intron_variant	Intron 5 of 5
LOC101927947	XR_007058336.1 link	n.4255+29199C>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.8400G>A	p.Pro2800Pro	synonymous_variant	Exon 20 of 20	1	NM_001358235.2	ENSP00000349768.5		Q6V1P9-1

Frequencies

GnomAD3 genomes

AF:

0.00669

AC:

1017

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0235

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00185

AC:

463

AN:

250340

Hom.:

AF XY:

0.00141

AC XY:

191

AN XY:

135272

show subpopulations

Gnomad AFR exome

AF:

0.0243

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00209

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.0000620

Gnomad OTH exome

AF:

0.000984

GnomAD4 exome

AF:

0.000787

AC:

1151

AN:

1461720

Hom.:

Cov.:

AF XY:

0.000694

AC XY:

505

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.0263

Gnomad4 AMR exome

AF:

0.00110

Gnomad4 ASJ exome

AF:

0.00184

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000495

Gnomad4 OTH exome

AF:

0.00156

GnomAD4 genome

AF:

0.00673

AC:

1024

AN:

152216

Hom.:

Cov.:

AF XY:

0.00656

AC XY:

488

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.0236

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00297

Hom.:

Bravo

AF:

0.00770

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

DCHS2-related disorder

Benign:1

Jun 07, 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

BayesDel_noAF

Benign

-0.74

CADD

Benign

6.9

DANN

Benign

0.24

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