Genetic Variant HAND2:p.Glu67Lys (chr4-173529091-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021973.3(HAND2):c.199G>A(p.Glu67Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000736 in 1,359,164 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

HAND2
NM_021973.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.81

Publications

0 publications found

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-AS1 (HGNC:48872): (HAND2 antisense RNA 1) Predicted to be involved in positive regulation of gene expression. Predicted to act upstream of or within with a positive effect on cardiac right ventricle morphogenesis. Predicted to act upstream of or within transcription elongation from RNA polymerase II promoter. Predicted to be located in chromatin; cytoplasm; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

HAND2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAND2	NM_021973.3 link	c.199G>A	p.Glu67Lys	missense_variant	Exon 1 of 2	ENST00000359562.4	NP_068808.1	P61296-1
HAND2-AS1	NR_136197.1 link	n.240+252C>T		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAND2	ENST00000359562.4 link	c.199G>A	p.Glu67Lys	missense_variant	Exon 1 of 2	1	NM_021973.3	ENSP00000352565.4		P61296-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.36e-7

AC:

AN:

1359164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

672130

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27336

American (AMR)

AF:

0.00

AC:

AN:

25236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19868

East Asian (EAS)

AF:

0.00

AC:

AN:

36426

South Asian (SAS)

AF:

0.00

AC:

AN:

68842

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48248

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3946

European-Non Finnish (NFE)

AF:

9.31e-7

AC:

AN:

1073688

Other (OTH)

AF:

0.00

AC:

AN:

55574

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;.

Eigen

Benign

-0.083

Eigen_PC

Benign

0.0085

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

T;D

M_CAP

Pathogenic

0.92

MetaRNN

Uncertain

0.47

T;T

MetaSVM

Uncertain

0.40

MutationAssessor

Uncertain

2.0

M;.

PhyloP100

5.8

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-1.4

N;.

REVEL

Uncertain

0.59

Sift

Benign

0.28

T;.

Sift4G

Benign

0.23

T;T

Polyphen

0.45

B;.

Vest4

0.33

MutPred

0.31

Gain of ubiquitination at E67 (P = 0.0082);Gain of ubiquitination at E67 (P = 0.0082);

MVP

0.92

MPC

1.1

ClinPred

0.87

GERP RS

3.9

Varity_R

0.43

gMVP

0.71

Mutation Taster

=73/27

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over