12-57449928-G-A

Variant names:

• chr12-57449928-G-A
• rs2229357
• NM_005538.4:c.965G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005538.4(INHBC):​c.965G>A​(p.Arg322Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,589,440 control chromosomes in the GnomAD database, including 42,225 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.19 (3132 hom., cov: 32)
  • Exomes 𝑓: 0.22 (39093 hom.)
• Consequence: INHBC NM_005538.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.42

Genes affected

INHBC (HGNC:6068): (inhibin subunit beta C) 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 homodimeric and heterodimeric activin complexes. The heterodimeric complex may function in the inhibition of activin A signaling. Transgenic mice overexpressing this gene exhibit defects in testis, liver and prostate. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042420924).
• BP6: Variant 12-57449928-G-A is Benign according to our data. Variant chr12-57449928-G-A is described in ClinVar as [Benign]. Clinvar id is 1226227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INHBC	NM_005538.4	c.965G>A	p.Arg322Gln	missense_variant	Exon 2 of 2	ENST00000309668.3	NP_005529.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INHBC	ENST00000309668.3	c.965G>A	p.Arg322Gln	missense_variant	Exon 2 of 2	1	NM_005538.4	ENSP00000308716.2

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28321 AN: 151996 Hom.: 3124 Cov.: 32

Gnomad AFR AF: 0.0933

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.0796

Gnomad SAS AF: 0.0820

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.232

Gnomad OTH AF: 0.174

GnomAD2 exomes AF: 0.216 AC: 50291 AN: 232398 AF XY: 0.204

Gnomad AFR exome AF: 0.0907

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.156

Gnomad EAS exome AF: 0.0708

Gnomad FIN exome AF: 0.226

Gnomad NFE exome AF: 0.232

Gnomad OTH exome AF: 0.205

GnomAD4 exome AF: 0.222 AC: 319221 AN: 1437326 Hom.: 39093 Cov.: 36 AF XY: 0.216 AC XY: 153872 AN XY: 712212

Gnomad4 AFR exome AF: 0.0850 AC: 2798 AN: 32912

Gnomad4 AMR exome AF: 0.409 AC: 17028 AN: 41656

Gnomad4 ASJ exome AF: 0.152 AC: 3721 AN: 24456

Gnomad4 EAS exome AF: 0.0808 AC: 3185 AN: 39416

Gnomad4 SAS exome AF: 0.0888 AC: 7357 AN: 82820

Gnomad4 FIN exome AF: 0.230 AC: 12040 AN: 52408

Gnomad4 NFE exome AF: 0.238 AC: 261467 AN: 1098710

Gnomad4 Remaining exome AF: 0.190 AC: 11247 AN: 59318

GnomAD4 genome AF: 0.186 AC: 28342 AN: 152114 Hom.: 3132 Cov.: 32 AF XY: 0.183 AC XY: 13641 AN XY: 74388

Gnomad4 AFR AF: 0.0933 AC: 0.0932771 AN: 0.0932771

Gnomad4 AMR AF: 0.279 AC: 0.279335 AN: 0.279335

Gnomad4 ASJ AF: 0.159 AC: 0.159366 AN: 0.159366

Gnomad4 EAS AF: 0.0794 AC: 0.0794356 AN: 0.0794356

Gnomad4 SAS AF: 0.0814 AC: 0.0814002 AN: 0.0814002

Gnomad4 FIN AF: 0.230 AC: 0.230385 AN: 0.230385

Gnomad4 NFE AF: 0.232 AC: 0.231782 AN: 0.231782

Gnomad4 OTH AF: 0.172 AC: 0.172201 AN: 0.172201

Alfa AF: 0.210 Hom.: 5629

Bravo AF: 0.194

TwinsUK AF: 0.243 AC: 901

ALSPAC AF: 0.236 AC: 909

ESP6500AA AF: 0.0956 AC: 421

ESP6500EA AF: 0.227 AC: 1950

ExAC AF: 0.209 AC: 25362

Asia WGS AF: 0.105 AC: 366 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30315176) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.12
Sift	Benign	0.065	T
Sift4G	Uncertain	0.057	T
Polyphen		0.28	B
Vest4		0.056
MPC		0.49
ClinPred		0.014	T
GERP RS		2.4
Varity_R		0.33
gMVP		0.82
Mutation Taster		=94/6	polymorphism (auto)

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: rs2229357; hg19: chr12-57843711; COSMIC: COSV59005215; COSMIC: COSV59005215;