4-173529091-C-T

Position:

• chr4-173529091-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.81

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAND2	NM_021973.3	c.199G>A	p.Glu67Lys	missense_variant	1/2	ENST00000359562.4	NP_068808.1
HAND2-AS1	NR_136197.1	n.240+252C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAND2	ENST00000359562.4	c.199G>A	p.Glu67Lys	missense_variant	1/2	1	NM_021973.3	ENSP00000352565.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.36e-7 AC: 1 AN: 1359164 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 672130

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.31e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;.
Eigen	Benign	-0.083
Eigen_PC	Benign	0.0085
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.0	M;.
PrimateAI	Pathogenic	0.94	D
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	D
GERP RS		3.9
Varity_R		0.43
gMVP		0.71

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: rs1553974835; hg19: chr4-174450242;