X-86651051-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.63

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]

ACMG classification

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: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High Hemizygotes in GnomAd at 16 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DACH2	NM_053281.3	c.656C>T	p.Ala219Val	missense_variant	4/12	ENST00000373125.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DACH2	ENST00000373125.9	c.656C>T	p.Ala219Val	missense_variant	4/12	1	NM_053281.3	A2

Frequencies

GnomAD3 genomes AF: 0.000439 AC: 49 AN: 111681 Hom.: 0 Cov.: 23 AF XY: 0.000472 AC XY: 16 AN XY: 33891

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.: 0 AF XY: 0.000565 AC XY: 33 AN XY: 58386

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.: 2 Cov.: 28 AF XY: 0.000365 AC XY: 131 AN XY: 358463

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: 49 AN: 111681 Hom.: 0 Cov.: 23 AF XY: 0.000472 AC XY: 16 AN XY: 33891

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.: 34

Bravo AF: 0.000348

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000743 AC: 5

ExAC AF: 0.000552 AC: 67

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

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	T
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	25
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.015	T;T;T;T
MetaSVM	Uncertain	0.23	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
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	T
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

Other links and lift over

dbSNP: rs151230279; hg19: chrX-85906054; COSMIC: COSV100913593;