2-120346598-A-G

Position:

• chr2-120346598-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002193.4(INHBB):​c.410A>G​(p.Gln137Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000768 in 1,302,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: INHBB NM_002193.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.20

Genes affected

INHBB (HGNC:6067): (inhibin subunit beta B) This gene encodes a member of the TGF-beta (transforming growth factor-beta) superfamily of proteins. The encoded preproprotein is proteolytically processed to generate a subunit of the dimeric activin and inhibin protein complexes. These complexes activate and inhibit, respectively, follicle stimulating hormone secretion from the pituitary gland. Polymorphisms near this gene are associated with pre-eclampsia in female human patients. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14636654).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INHBB	NM_002193.4	c.410A>G	p.Gln137Arg	missense_variant	1/2	ENST00000295228.4	NP_002184.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INHBB	ENST00000295228.4	c.410A>G	p.Gln137Arg	missense_variant	1/2	1	NM_002193.4	ENSP00000295228.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.68e-7 AC: 1 AN: 1302086 Hom.: 0 Cov.: 33 AF XY: 0.00000157 AC XY: 1 AN XY: 637742

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000318

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 03, 2024

The c.410A>G (p.Q137R) alteration is located in exon 1 (coding exon 1) of the INHBB gene. This alteration results from a A to G substitution at nucleotide position 410, causing the glutamine (Q) at amino acid position 137 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Benign	0.78
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.5	L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.24
Sift	Benign	0.48	T
Sift4G	Benign	0.51	T
Polyphen		0.010	B
Vest4		0.070
MutPred		0.49		Loss of loop (P = 0.0804);
MVP		0.83
MPC		0.74
ClinPred		0.067	T
GERP RS		3.3
Varity_R		0.16
gMVP		0.37

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: rs931631684; hg19: chr2-121104174;