Variant 4-173529007-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_021973.3(HAND2):c.283C>G(p.Pro95Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000195 in 1,591,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

HAND2
NM_021973.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.59

Variant links:

Genes affected

HAND2 (HGNC:4808): (heart and neural crest derivatives expressed 2) The protein encoded by this gene belongs to the basic helix-loop-helix family of transcription factors. This gene product is one of two closely related family members, the HAND proteins, which are asymmetrically expressed in the developing ventricular chambers and play an essential role in cardiac morphogenesis. Working in a complementary fashion, they function in the formation of the right ventricle and aortic arch arteries, implicating them as mediators of congenital heart disease. In addition, this transcription factor plays an important role in limb and branchial arch development. [provided by RefSeq, Jul 2008]

HAND2 links:

HAND2 (HGNC:):

HAND2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23232064).

BS2

High AC in GnomAdExome4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAND2	NM_021973.3 linkuse as main transcript	c.283C>G	p.Pro95Ala	missense_variant	1/2	ENST00000359562.4	NP_068808.1	P61296-1
HAND2-AS1	NR_136197.1 linkuse as main transcript	n.240+168G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAND2	ENST00000359562.4 linkuse as main transcript	c.283C>G	p.Pro95Ala	missense_variant	1/2	1	NM_021973.3	ENSP00000352565.4		P61296-1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151772

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000231

AC:

AN:

216798

Hom.:

AF XY:

0.0000419

AC XY:

AN XY:

119442

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000113

Gnomad FIN exome

AF:

0.0000483

Gnomad NFE exome

AF:

0.0000104

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000195

AC:

AN:

1439458

Hom.:

Cov.:

AF XY:

0.0000196

AC XY:

AN XY:

715170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000605

Gnomad4 FIN exome

AF:

0.0000763

Gnomad4 NFE exome

AF:

0.0000145

Gnomad4 OTH exome

AF:

0.0000507

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151772

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74098

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000336

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 22, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with HAND2-related conditions. This variant is present in population databases (rs75152023, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 95 of the HAND2 protein (p.Pro95Ala). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Benign

0.87

DEOGEN2

Benign

0.39

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.64

M_CAP

Pathogenic

0.55

MetaRNN

Benign

0.23

MetaSVM

Uncertain

0.13

MutationAssessor

Benign

1.6

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.37

Sift

Benign

0.15

Sift4G

Uncertain

0.028

Polyphen

0.0010

Vest4

0.16

MutPred

0.19

Gain of helix (P = 0.0325);

MVP

1.0

MPC

0.92

ClinPred

0.064

GERP RS

4.0

Varity_R

0.11

gMVP

0.57

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