Genetic Variant NM_001322331.2:c.136A>G (chr2-119321202-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. 14/20 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.

Frequency

Genomes: 𝑓 0.70 ( 37084 hom., cov: 32)

Exomes 𝑓: 0.64 ( 257190 hom. )

Consequence

C2orf76
NM_001322331.2 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.23

Publications

31 publications found

Variant links:

Genes affected

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

C2orf76 links:

ENSG00000309372 (HGNC:):

ENSG00000309372 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
C2orf76	NM_001322331.2 link	c.136A>G	p.Ile46Val	missense_variant, splice_region_variant	Exon 3 of 6	ENST00000334816.12	NP_001309260.1	Q3KRA6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C2orf76	ENST00000334816.12 link	c.136A>G	p.Ile46Val	missense_variant, splice_region_variant	Exon 3 of 6	1	NM_001322331.2	ENSP00000335041.7		Q3KRA6

Frequencies

GnomAD3 genomes

AF:

0.695

AC:

105377

AN:

151574

Hom.:

37022

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.653

AC:

130883

AN:

200508

AF XY:

0.654

show subpopulations

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 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.:

AF XY:

0.646

AC XY:

398221

AN XY:

616778

show subpopulations

African (AFR)

AF:

0.790

AC:

18361

AN:

23254

American (AMR)

AF:

0.598

AC:

19029

AN:

31798

Ashkenazi Jewish (ASJ)

AF:

0.607

AC:

14181

AN:

23350

East Asian (EAS)

AF:

0.419

AC:

14780

AN:

35288

South Asian (SAS)

AF:

0.671

AC:

46428

AN:

69190

European-Finnish (FIN)

AF:

0.764

AC:

39229

AN:

51360

Middle Eastern (MID)

AF:

0.662

AC:

3385

AN:

5110

European-Non Finnish (NFE)

AF:

0.642

AC:

600952

AN:

935340

Other (OTH)

AF:

0.641

AC:

32907

AN:

51322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

10669

21338

32006

42675

53344

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15040

30080

45120

60160

75200

<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:

0.695

AC:

105499

AN:

151694

Hom.:

37084

Cov.:

AF XY:

0.699

AC XY:

51825

AN XY:

74176

show subpopulations

African (AFR)

AF:

0.807

AC:

33486

AN:

41496

American (AMR)

AF:

0.622

AC:

9468

AN:

15212

Ashkenazi Jewish (ASJ)

AF:

0.620

AC:

2145

AN:

3462

East Asian (EAS)

AF:

0.458

AC:

2370

AN:

5176

South Asian (SAS)

AF:

0.676

AC:

3262

AN:

4824

European-Finnish (FIN)

AF:

0.756

AC:

7968

AN:

10540

Middle Eastern (MID)

AF:

0.653

AC:

192

AN:

294

European-Non Finnish (NFE)

AF:

0.659

AC:

44583

AN:

67678

Other (OTH)

AF:

0.643

AC:

1351

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1654

3308

4962

6616

8270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

820

1640

2460

3280

4100

<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:

0.665

Hom.:

69229

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

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.11

(source)

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

LIST_S2

Benign

0.27

.;.;.;T;T

MetaRNN

Benign

6.3e-7

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.33

N;N;N;N;.

PhyloP100

-1.2

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

GERP RS

-2.9

Varity_R

0.025

gMVP

0.33

Mutation Taster

=97/3

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over