rs17373860

Positions:

• chr4-154490731-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001358235.2(DCHS2):​c.625C>T​(p.Pro209Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0692 in 1,551,632 control chromosomes in the GnomAD database, including 4,412 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.058 (407 hom., cov: 33)
  • Exomes 𝑓: 0.070 (4005 hom.)
• Consequence: DCHS2 NM_001358235.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.800

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014812648).
• BP6: Variant 4-154490731-G-A is Benign according to our data. Variant chr4-154490731-G-A is described in ClinVar as [Benign]. Clinvar id is 3059143.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCHS2	NM_001358235.2	c.625C>T	p.Pro209Ser	missense_variant	1/20	ENST00000357232.10
DCHS2	NM_001142552.2	c.625C>T	p.Pro209Ser	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCHS2	ENST00000357232.10	c.625C>T	p.Pro209Ser	missense_variant	1/20	1	NM_001358235.2	P1
DCHS2	ENST00000339452.2	c.625C>T	p.Pro209Ser	missense_variant	1/8	1
DCHS2	ENST00000456341.2	n.604C>T		non_coding_transcript_exon_variant	1/2	1

Frequencies

GnomAD3 genomes AF: 0.0581 AC: 8836 AN: 152212 Hom.: 407 Cov.: 33

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.0715

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0283

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0764

Gnomad OTH AF: 0.0483

GnomAD3 exomes AF: 0.0690 AC: 10577 AN: 153180 Hom.: 557 AF XY: 0.0658 AC XY: 5358 AN XY: 81438

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.0996

Gnomad ASJ exome AF: 0.0359

Gnomad EAS exome AF: 0.000276

Gnomad SAS exome AF: 0.0352

Gnomad FIN exome AF: 0.157

Gnomad NFE exome AF: 0.0721

Gnomad OTH exome AF: 0.0593

GnomAD4 exome AF: 0.0704 AC: 98531 AN: 1399302 Hom.: 4005 Cov.: 92 AF XY: 0.0692 AC XY: 47769 AN XY: 690170

Gnomad4 AFR exome AF: 0.0101

Gnomad4 AMR exome AF: 0.0981

Gnomad4 ASJ exome AF: 0.0385

Gnomad4 EAS exome AF: 0.000532

Gnomad4 SAS exome AF: 0.0345

Gnomad4 FIN exome AF: 0.150

Gnomad4 NFE exome AF: 0.0743

Gnomad4 OTH exome AF: 0.0580

GnomAD4 genome AF: 0.0581 AC: 8849 AN: 152330 Hom.: 407 Cov.: 33 AF XY: 0.0598 AC XY: 4452 AN XY: 74486

Gnomad4 AFR AF: 0.0114

Gnomad4 AMR AF: 0.0718

Gnomad4 ASJ AF: 0.0360

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.0290

Gnomad4 FIN AF: 0.149

Gnomad4 NFE AF: 0.0764

Gnomad4 OTH AF: 0.0478

Alfa AF: 0.0657 Hom.: 542

Bravo AF: 0.0504

TwinsUK AF: 0.0717 AC: 266

ALSPAC AF: 0.0651 AC: 251

ESP6500AA AF: 0.0101 AC: 14

ESP6500EA AF: 0.0817 AC: 260

ExAC AF: 0.0454 AC: 1183

Asia WGS AF: 0.0200 AC: 71 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DCHS2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2019

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	0.085
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.6
DANN	Benign	0.91
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.25	N
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N
Vest4		0.024
ClinPred		0.0059	T
GERP RS		-0.34
gMVP		0.49

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17373860; hg19: chr4-155411883; COSMIC: COSV59728481;