chr4-173529000-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_021973.3(HAND2):c.290C>G(p.Pro97Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000472 in 1,609,850 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P97P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

HAND2
NM_021973.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.95

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021973.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAND2	NM_021973.3	MANE Select	c.290C>G	p.Pro97Arg	missense	Exon 1 of 2	NP_068808.1	P61296-1
	HAND2-AS1	NR_136197.1		n.240+161G>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HAND2	ENST00000359562.4	TSL:1 MANE Select	c.290C>G	p.Pro97Arg	missense	Exon 1 of 2	ENSP00000352565.4	P61296-1
HAND2	ENST00000505300.1	TSL:5	n.452C>G		non_coding_transcript_exon	Exon 3 of 3
HAND2-AS1	ENST00000512099.5	TSL:2	n.1232+499G>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151962

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000294

AC:

AN:

238440

AF XY:

0.0000307

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000192

Gnomad OTH exome

AF:

0.000171

GnomAD4 exome

AF:

0.0000480

AC:

AN:

1457888

Hom.:

Cov.:

AF XY:

0.0000510

AC XY:

AN XY:

724882

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33270

American (AMR)

AF:

0.000135

AC:

AN:

44486

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25994

East Asian (EAS)

AF:

0.000177

AC:

AN:

39550

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86026

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5278

European-Non Finnish (NFE)

AF:

0.0000486

AC:

AN:

1110326

Other (OTH)

AF:

0.0000333

AC:

AN:

60134

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151962

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41416

American (AMR)

AF:

0.000262

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5114

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67948

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.00000829

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

HAND2-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.0081

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Benign

0.69

DEOGEN2

Uncertain

0.43

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.082

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.74

M_CAP

Pathogenic

0.84

MetaRNN

Uncertain

0.49

MetaSVM

Uncertain

0.37

MutationAssessor

Benign

1.2

PhyloP100

6.0

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.48

Sift

Benign

0.28

Sift4G

Benign

0.46

Polyphen

0.64

Vest4

0.45

MutPred

0.22

Gain of MoRF binding (P = 0.0138)

MVP

0.95

MPC

1.2

ClinPred

0.11

GERP RS

4.0

Varity_R

0.13

gMVP

0.55

Mutation Taster

=70/30

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over