chrX-86651051-C-T

Position:

chrX-86651051-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_053281.3(DACH2):c.656C>T(p.Ala219Val) variant causes a missense change. The variant allele was found at a frequency of 0.000365 in 1,203,718 control chromosomes in the GnomAD database, including 2 homozygotes. There are 147 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., 16 hem., cov: 23)

Exomes 𝑓: 0.00036 ( 2 hom. 131 hem. )

Consequence

DACH2
NM_053281.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 5.63

Variant links:

Genes affected

DACH2 (HGNC:16814): (dachshund family transcription factor 2) This gene is one of two genes which encode a protein similar to the Drosophila protein dachshund, a transcription factor involved in cell fate determination in the eye, limb and genital disc of the fly. The encoded protein contains two characteristic dachshund domains: an N-terminal domain responsible for DNA binding and a C-terminal domain responsible for protein-protein interactions. This gene is located on the X chromosome and is subject to inactivation by DNA methylation. The encoded protein may be involved in regulation of organogenesis and myogenesis, and may play a role in premature ovarian failure. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2008]

DACH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014601916).

BP6

Variant X-86651051-C-T is Benign according to our data. Variant chrX-86651051-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2661008.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAd4 at 16 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DACH2	NM_053281.3 linkuse as main transcript	c.656C>T	p.Ala219Val	missense_variant	4/12	ENST00000373125.9	NP_444511.1	Q96NX9-1A8K3I1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DACH2	ENST00000373125.9 linkuse as main transcript	c.656C>T	p.Ala219Val	missense_variant	4/12	1	NM_053281.3	ENSP00000362217.4		Q96NX9-1

Frequencies

GnomAD3 genomes

AF:

0.000439

AC:

AN:

111681

Hom.:

Cov.:

AF XY:

0.000472

AC XY:

AN XY:

33891

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00947

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000996

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000320

Gnomad OTH

AF:

0.000671

GnomAD3 exomes

AF:

0.000654

AC:

113

AN:

172792

Hom.:

AF XY:

0.000565

AC XY:

AN XY:

58386

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00630

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000952

Gnomad NFE exome

AF:

0.000648

Gnomad OTH exome

AF:

0.000476

GnomAD4 exome

AF:

0.000357

AC:

390

AN:

1092037

Hom.:

Cov.:

AF XY:

0.000365

AC XY:

131

AN XY:

358463

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000577

Gnomad4 ASJ exome

AF:

0.00576

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000188

Gnomad4 FIN exome

AF:

0.00121

Gnomad4 NFE exome

AF:

0.000242

Gnomad4 OTH exome

AF:

0.000524

GnomAD4 genome

AF:

0.000439

AC:

AN:

111681

Hom.:

Cov.:

AF XY:

0.000472

AC XY:

AN XY:

33891

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00947

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000996

Gnomad4 NFE

AF:

0.000320

Gnomad4 OTH

AF:

0.000671

Alfa

AF:

0.000720

Hom.:

Bravo

AF:

0.000348

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000743

AC:

ExAC

AF:

0.000552

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2021

The c.656C>T (p.A219V) alteration is located in exon 4 (coding exon 4) of the DACH2 gene. This alteration results from a C to T substitution at nucleotide position 656, causing the alanine (A) at amino acid position 219 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

DACH2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

.;T;.;T

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.015

T;T;T;T

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.2

.;M;.;.

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-2.2

N;N;D;.

REVEL

Uncertain

0.52

Sift

Uncertain

0.012

D;D;D;.

Sift4G

Uncertain

0.021

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.56

MVP

0.90

MPC

0.28

ClinPred

0.11

GERP RS

4.7

Varity_R

0.58

gMVP

0.64

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