Genetic Variant ENST00000295171.10:c.364G>C (chr2-131530647-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000295171.10(CCDC74A):c.364G>C(p.Gly122Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,612,274 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.00099 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

CCDC74A
ENST00000295171.10 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.27

Publications

7 publications found

Variant links:

Genes affected

CCDC74A (HGNC:25197): (coiled-coil domain containing 74A)

CCDC74A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0061077774).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000295171.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC74A	NM_001258306.3	MANE Select	c.296-130G>C		intron	N/A	NP_001245235.1	Q96AQ1-2
CCDC74A	NM_001349042.2		c.490G>C	p.Gly164Arg	missense	Exon 3 of 8	NP_001335971.1
CCDC74A	NM_138770.4		c.364G>C	p.Gly122Arg	missense	Exon 3 of 8	NP_620125.1	Q96AQ1-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC74A	ENST00000295171.10	TSL:1	c.364G>C	p.Gly122Arg	missense	Exon 3 of 8	ENSP00000295171.6	Q96AQ1-1
CCDC74A	ENST00000467992.6	TSL:1	c.364G>C	p.Gly122Arg	missense	Exon 3 of 7	ENSP00000444610.2	F5GZA4
CCDC74A	ENST00000409856.8	TSL:1 MANE Select	c.296-130G>C		intron	N/A	ENSP00000387009.3	Q96AQ1-2

Frequencies

GnomAD3 genomes

AF:

0.000995

AC:

151

AN:

151690

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000316

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000591

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00991

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00103

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00118

AC:

288

AN:

243486

AF XY:

0.00104

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.000326

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00767

Gnomad FIN exome

AF:

0.000143

Gnomad NFE exome

AF:

0.00115

Gnomad OTH exome

AF:

0.000508

GnomAD4 exome

AF:

0.00121

AC:

1770

AN:

1460468

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

828

AN XY:

726524

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000179

AC:

AN:

33468

American (AMR)

AF:

0.000358

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.0000766

AC:

AN:

26122

East Asian (EAS)

AF:

0.00567

AC:

225

AN:

39648

South Asian (SAS)

AF:

0.000232

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.000510

AC:

AN:

52922

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00127

AC:

1408

AN:

1111358

Other (OTH)

AF:

0.00108

AC:

AN:

60336

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.320

Heterozygous variant carriers

102

204

305

407

509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

180

240

300

<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:

0.000995

AC:

151

AN:

151806

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

AN XY:

74208

show subpopulations

African (AFR)

AF:

0.000315

AC:

AN:

41284

American (AMR)

AF:

0.000590

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00994

AC:

AN:

5132

South Asian (SAS)

AF:

0.000208

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.000378

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00103

AC:

AN:

67970

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000475

Hom.:

ESP6500AA

AF:

0.000234

AC:

ESP6500EA

AF:

0.00130

AC:

ExAC

AF:

0.00126

AC:

152

EpiCase

AF:

0.00142

EpiControl

AF:

0.000713

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.91

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.0014

Eigen

Benign

-0.72

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0095

LIST_S2

Benign

0.64

M_CAP

Benign

0.0090

MetaRNN

Benign

0.0061

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.3

PhyloP100

-1.3

PROVEAN

Benign

-0.010

REVEL

Benign

0.038

Sift

Pathogenic

0.0

Sift4G

Benign

0.80

Polyphen

1.0

Vest4

0.097

MutPred

0.41

Gain of sheet (P = 0.0085)

MVP

0.33

MPC

1.8

ClinPred

0.031

GERP RS

-2.8

Varity_R

0.089

gMVP

0.12

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over