4-154235390-G-A

Variant names:

• chr4-154235390-G-A
• rs61741046
• NM_001358235.2:c.9262C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001358235.2(DCHS2):​c.9262C>T​(p.His3088Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0253 in 1,613,970 control chromosomes in the GnomAD database, including 771 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 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 (178 hom., cov: 32)
  • Exomes 𝑓: 0.024 (593 hom.)
• Consequence: DCHS2 NM_001358235.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 5.48
• Publications: 12 publications found

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]

ENSG00000280241 (HGNC:58900):

LOC101927947 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002567619).
• BP6: Variant 4-154235390-G-A is Benign according to our data. Variant chr4-154235390-G-A is described in ClinVar as Benign. ClinVar VariationId is 3056142.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0803 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001358235.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCHS2	NM_001358235.2	MANE Select	c.9262C>T	p.His3088Tyr	missense	Exon 20 of 20	NP_001345164.1	Q6V1P9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCHS2	ENST00000357232.10	TSL:1 MANE Select	c.9262C>T	p.His3088Tyr	missense	Exon 20 of 20	ENSP00000349768.5	Q6V1P9-1
	DCHS2	ENST00000623607.4	TSL:1	n.7896C>T		non_coding_transcript_exon	Exon 25 of 25
	ENSG00000280241	ENST00000623325.1	TSL:5	n.98+28337G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0403 AC: 6126 AN: 152076 Hom.: 176 Cov.: 32

Gnomad AFR AF: 0.0826

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0494

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.0472

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0219

Gnomad OTH AF: 0.0445

GnomAD2 exomes AF: 0.0271 AC: 6792 AN: 250796 AF XY: 0.0237

Gnomad AFR exome AF: 0.0812

Gnomad AMR exome AF: 0.0462

Gnomad ASJ exome AF: 0.0219

Gnomad EAS exome AF: 0.0426

Gnomad FIN exome AF: 0.00397

Gnomad NFE exome AF: 0.0223

Gnomad OTH exome AF: 0.0322

GnomAD4 exome AF: 0.0238 AC: 34754 AN: 1461776 Hom.: 593 Cov.: 34 AF XY: 0.0226 AC XY: 16443 AN XY: 727198

African (AFR) AF: 0.0841 AC: 2814 AN: 33476

American (AMR) AF: 0.0469 AC: 2096 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0203 AC: 531 AN: 26132

East Asian (EAS) AF: 0.0625 AC: 2480 AN: 39686

South Asian (SAS) AF: 0.00240 AC: 207 AN: 86258

European-Finnish (FIN) AF: 0.00440 AC: 235 AN: 53412

Middle Eastern (MID) AF: 0.0277 AC: 160 AN: 5766

European-Non Finnish (NFE) AF: 0.0221 AC: 24627 AN: 1111944

Other (OTH) AF: 0.0266 AC: 1604 AN: 60386

GnomAD4 genome AF: 0.0403 AC: 6134 AN: 152194 Hom.: 178 Cov.: 32 AF XY: 0.0387 AC XY: 2877 AN XY: 74408

African (AFR) AF: 0.0826 AC: 3427 AN: 41504

American (AMR) AF: 0.0492 AC: 751 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3472

East Asian (EAS) AF: 0.0473 AC: 245 AN: 5180

South Asian (SAS) AF: 0.00312 AC: 15 AN: 4814

European-Finnish (FIN) AF: 0.00330 AC: 35 AN: 10606

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0219 AC: 1492 AN: 68020

Other (OTH) AF: 0.0449 AC: 95 AN: 2114

Alfa AF: 0.0287 Hom.: 187

Bravo AF: 0.0447

TwinsUK AF: 0.0216 AC: 80

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.0826 AC: 364

ESP6500EA AF: 0.0202 AC: 174

ExAC AF: 0.0276 AC: 3355

Asia WGS AF: 0.0440 AC: 153 AN: 3478

EpiCase AF: 0.0205

EpiControl AF: 0.0216

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	DCHS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.2	T
PhyloP100		5.5
PrimateAI	Benign	0.36	T
REVEL	Benign	0.17
MPC		0.35
ClinPred		0.035	T
GERP RS		5.5
gMVP		0.27
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61741046; hg19: chr4-155156542; COSMIC: COSV61770596;