Genetic Variant CCDC74B:p.Ala189Gly (chr2-130140291-G-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001258307.2(CCDC74B):c.566C>G(p.Ala189Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 151,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A189V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00089 ( 9 hom. )

Failed GnomAD Quality Control

Consequence

CCDC74B
NM_001258307.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0240

Publications

5 publications found

Variant links:

Genes affected

CCDC74B (HGNC:25267): (coiled-coil domain containing 74B)

CCDC74B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024977416).

BP6

Variant 2-130140291-G-C is Benign according to our data. Variant chr2-130140291-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2349338.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001258307.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC74B	NM_001258307.2	MANE Select	c.566C>G	p.Ala189Gly	missense	Exon 5 of 8	NP_001245236.1	Q96LY2-2
CCDC74B	NM_207310.4		c.764C>G	p.Ala255Gly	missense	Exon 5 of 8	NP_997193.1	Q96LY2-1
CCDC74B	NR_165309.1		n.849C>G		non_coding_transcript_exon	Exon 5 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC74B	ENST00000409943.8	TSL:1 MANE Select	c.566C>G	p.Ala189Gly	missense	Exon 5 of 8	ENSP00000386294.3	Q96LY2-2
CCDC74B	ENST00000860854.1		c.776C>G	p.Ala259Gly	missense	Exon 5 of 8	ENSP00000530913.1
CCDC74B	ENST00000944366.1		c.776C>G	p.Ala259Gly	missense	Exon 5 of 8	ENSP00000614425.1

Frequencies

GnomAD3 genomes

AF:

0.00144

AC:

217

AN:

151078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000789

Gnomad ASJ

AF:

0.00466

Gnomad EAS

AF:

0.00195

Gnomad SAS

AF:

0.00188

Gnomad FIN

AF:

0.000852

Gnomad MID

AF:

0.00323

Gnomad NFE

AF:

0.00158

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000550

AC:

137

AN:

249044

AF XY:

0.000543

show subpopulations

Gnomad AFR exome

AF:

0.000678

Gnomad AMR exome

AF:

0.000784

Gnomad ASJ exome

AF:

0.00111

Gnomad EAS exome

AF:

0.000436

Gnomad FIN exome

AF:

0.0000928

Gnomad NFE exome

AF:

0.000446

Gnomad OTH exome

AF:

0.000824

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000886

AC:

1292

AN:

1457558

Hom.:

Cov.:

AF XY:

0.000924

AC XY:

670

AN XY:

725068

show subpopulations

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

African (AFR)

AF:

0.000509

AC:

AN:

33392

American (AMR)

AF:

0.00123

AC:

AN:

44584

Ashkenazi Jewish (ASJ)

AF:

0.00374

AC:

AN:

25910

East Asian (EAS)

AF:

0.00517

AC:

205

AN:

39654

South Asian (SAS)

AF:

0.00138

AC:

119

AN:

86026

European-Finnish (FIN)

AF:

0.000771

AC:

AN:

53192

Middle Eastern (MID)

AF:

0.000889

AC:

AN:

5624

European-Non Finnish (NFE)

AF:

0.000601

AC:

666

AN:

1109008

Other (OTH)

AF:

0.00145

AC:

AN:

60168

⚠️ 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: 0.328

Heterozygous variant carriers

119

178

238

297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00144

AC:

218

AN:

151200

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

101

AN XY:

73906

show subpopulations

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

African (AFR)

AF:

0.00124

AC:

AN:

41120

American (AMR)

AF:

0.000788

AC:

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.00466

AC:

AN:

3436

East Asian (EAS)

AF:

0.00195

AC:

AN:

5128

South Asian (SAS)

AF:

0.00188

AC:

AN:

4780

European-Finnish (FIN)

AF:

0.000852

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00345

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00158

AC:

107

AN:

67650

Other (OTH)

AF:

0.00143

AC:

AN:

2102

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.345

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:

0.000765

Hom.:

ExAC

AF:

0.000214

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.047

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.63

CADD

Benign

7.9

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.00048

Eigen

Benign

-2.4

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.0084

LIST_S2

Benign

0.22

M_CAP

Benign

0.0024

MetaRNN

Benign

0.025

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

PhyloP100

-0.024

PrimateAI

Benign

0.40

PROVEAN

Benign

0.89

REVEL

Benign

0.037

Sift

Benign

0.85

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.12

MVP

0.21

MPC

1.4

ClinPred

0.00030

GERP RS

-1.4

Varity_R

0.023

gMVP

0.030

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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