chr12-57449928-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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 42 publications found

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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005538.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INHBC	NM_005538.4	MANE Select	c.965G>A	p.Arg322Gln	missense	Exon 2 of 2	NP_005529.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INHBC	ENST00000309668.3	TSL:1 MANE Select	c.965G>A	p.Arg322Gln	missense	Exon 2 of 2	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

African (AFR) AF: 0.0850 AC: 2798 AN: 32912

American (AMR) AF: 0.409 AC: 17028 AN: 41656

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 3721 AN: 24456

East Asian (EAS) AF: 0.0808 AC: 3185 AN: 39416

South Asian (SAS) AF: 0.0888 AC: 7357 AN: 82820

European-Finnish (FIN) AF: 0.230 AC: 12040 AN: 52408

Middle Eastern (MID) AF: 0.0671 AC: 378 AN: 5630

European-Non Finnish (NFE) AF: 0.238 AC: 261467 AN: 1098710

Other (OTH) 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

African (AFR) AF: 0.0933 AC: 3871 AN: 41500

American (AMR) AF: 0.279 AC: 4266 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 553 AN: 3470

East Asian (EAS) AF: 0.0794 AC: 411 AN: 5174

South Asian (SAS) AF: 0.0814 AC: 393 AN: 4828

European-Finnish (FIN) AF: 0.230 AC: 2443 AN: 10604

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.232 AC: 15751 AN: 67956

Other (OTH) AF: 0.172 AC: 363 AN: 2108

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.4
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

Other links and lift over

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