rs6542522

chr2-119321202-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001322331.2(C2orf76):c.136A>G(p.Ile46Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.649 in 1,377,706 control chromosomes in the GnomAD database, including 294,274 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.70 (37084 hom., cov: 32)
  • Exomes 𝑓: 0.64 (257190 hom.)
• Consequence: C2orf76 NM_001322331.2 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.23

Genes affected

C2orf76 (HGNC:27017): (chromosome 2 open reading frame 76)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.3377E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C2orf76	NM_001322331.2	c.136A>G	p.Ile46Val	missense_variant, splice_region_variant	3/6	ENST00000334816.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C2orf76	ENST00000334816.12	c.136A>G	p.Ile46Val	missense_variant, splice_region_variant	3/6	1	NM_001322331.2	P1

Frequencies

GnomAD3 genomes AF: 0.695 AC: 105377 AN: 151574 Hom.: 37022 Cov.: 32

Gnomad AFR AF: 0.807

Gnomad AMI AF: 0.739

Gnomad AMR AF: 0.622

Gnomad ASJ AF: 0.620

Gnomad EAS AF: 0.458

Gnomad SAS AF: 0.676

Gnomad FIN AF: 0.756

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.659

Gnomad OTH AF: 0.642

GnomAD3 exomes AF: 0.653 AC: 130883 AN: 200508 Hom.: 43613 AF XY: 0.654 AC XY: 72319 AN XY: 110500

Gnomad AFR exome AF: 0.805

Gnomad AMR exome AF: 0.593

Gnomad ASJ exome AF: 0.616

Gnomad EAS exome AF: 0.414

Gnomad SAS exome AF: 0.671

Gnomad FIN exome AF: 0.760

Gnomad NFE exome AF: 0.656

Gnomad OTH exome AF: 0.651

GnomAD4 exome AF: 0.644 AC: 789252 AN: 1226012 Hom.: 257190 Cov.: 20 AF XY: 0.646 AC XY: 398221 AN XY: 616778

Gnomad4 AFR exome AF: 0.790

Gnomad4 AMR exome AF: 0.598

Gnomad4 ASJ exome AF: 0.607

Gnomad4 EAS exome AF: 0.419

Gnomad4 SAS exome AF: 0.671

Gnomad4 FIN exome AF: 0.764

Gnomad4 NFE exome AF: 0.642

Gnomad4 OTH exome AF: 0.641

GnomAD4 genome AF: 0.695 AC: 105499 AN: 151694 Hom.: 37084 Cov.: 32 AF XY: 0.699 AC XY: 51825 AN XY: 74176

Gnomad4 AFR AF: 0.807

Gnomad4 AMR AF: 0.622

Gnomad4 ASJ AF: 0.620

Gnomad4 EAS AF: 0.458

Gnomad4 SAS AF: 0.676

Gnomad4 FIN AF: 0.756

Gnomad4 NFE AF: 0.659

Gnomad4 OTH AF: 0.643

Alfa AF: 0.656 Hom.: 45551

Bravo AF: 0.687

TwinsUK AF: 0.647 AC: 2400

ALSPAC AF: 0.658 AC: 2536

ESP6500AA AF: 0.804 AC: 2880

ESP6500EA AF: 0.659 AC: 5362

ExAC AF: 0.664 AC: 79983

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.11
Dann	Benign	0.76
DEOGEN2	Benign	0.012	T;T;T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0028	N
MetaRNN	Benign	6.3e-7	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.33	N;N;N;N;.
MutationTaster	Benign	1.0	P;P;P;P
PROVEAN	Benign	-0.15	N;N;N;N;N
REVEL	Benign	0.039
Sift	Benign	0.72	T;T;T;T;T
Sift4G	Benign	0.91	T;T;T;T;.
Polyphen		0.0040	B;B;B;B;.
Vest4		0.011
MPC		0.049
ClinPred		0.00070	T
GERP RS		-2.9
Varity_R		0.025
gMVP		0.33

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: rs1132267; hg19: chr2-120078778; COSMIC: COSV58345432;