Genetic Variant CCDC74B:p.Arg308Pro (chr2-130139577-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001258307.2(CCDC74B):c.923G>C(p.Arg308Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R308H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CCDC74B
NM_001258307.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.54

Publications

3 publications found

Variant links:

Genes affected

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

CCDC74B links:

MED15P9 (HGNC:):

MED15P9 links:

MED15P9 (HGNC:44130): (mediator complex subunit 15 pseudogene 9)

MED15P9 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.838

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.923G>C	p.Arg308Pro	missense	Exon 8 of 8	NP_001245236.1	Q96LY2-2
CCDC74B	NM_207310.4		c.1121G>C	p.Arg374Pro	missense	Exon 8 of 8	NP_997193.1	Q96LY2-1
CCDC74B	NR_165309.1		n.1206G>C		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC74B	ENST00000409943.8	TSL:1 MANE Select	c.923G>C	p.Arg308Pro	missense	Exon 8 of 8	ENSP00000386294.3	Q96LY2-2
CCDC74B	ENST00000860854.1		c.1133G>C	p.Arg378Pro	missense	Exon 8 of 8	ENSP00000530913.1
CCDC74B	ENST00000944366.1		c.1133G>C	p.Arg378Pro	missense	Exon 8 of 8	ENSP00000614425.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.84e-7

AC:

AN:

1461006

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726784

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52774

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5646

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111974

Other (OTH)

AF:

0.00

AC:

AN:

60354

⚠️ 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: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.063

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.78

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.84

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.6

PhyloP100

1.5

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.61

MVP

0.83

MPC

0.71

ClinPred

0.99

GERP RS

4.2

Varity_R

0.75

gMVP

0.21

Mutation Taster

=78/22

polymorphism

(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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over