Genetic Variant CCDC74B:p.Asp252Asn (chr2-130139946-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001258307.2(CCDC74B):c.754G>A(p.Asp252Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,459,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. D252H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CCDC74B
NM_001258307.2 missense, splice_region

Scores

Splicing: ADA: 0.6188

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.573

Publications

0 publications found

Variant links:

Genes affected

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

CCDC74B links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22889096).

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.754G>A	p.Asp252Asn	missense splice_region	Exon 7 of 8	NP_001245236.1	Q96LY2-2
CCDC74B	NM_207310.4		c.952G>A	p.Asp318Asn	missense splice_region	Exon 7 of 8	NP_997193.1	Q96LY2-1
CCDC74B	NR_165309.1		n.1037G>A		splice_region non_coding_transcript_exon	Exon 7 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC74B	ENST00000409943.8	TSL:1 MANE Select	c.754G>A	p.Asp252Asn	missense splice_region	Exon 7 of 8	ENSP00000386294.3	Q96LY2-2
CCDC74B	ENST00000860854.1		c.964G>A	p.Asp322Asn	missense splice_region	Exon 7 of 8	ENSP00000530913.1
CCDC74B	ENST00000944366.1		c.964G>A	p.Asp322Asn	missense splice_region	Exon 7 of 8	ENSP00000614425.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000805

AC:

AN:

248426

AF XY:

0.00000744

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000201

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1459884

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

726098

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44548

Ashkenazi Jewish (ASJ)

AF:

0.0000767

AC:

AN:

26062

East Asian (EAS)

AF:

0.00

AC:

AN:

39660

South Asian (SAS)

AF:

0.00

AC:

AN:

86064

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53098

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111004

Other (OTH)

AF:

0.0000166

AC:

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0025

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.77

M_CAP

Benign

0.070

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.4

PhyloP100

0.57

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.8

REVEL

Benign

0.11

Sift

Uncertain

0.022

Sift4G

Benign

0.072

Polyphen

0.73

Vest4

0.39

MVP

0.65

MPC

0.57

ClinPred

0.72

GERP RS

2.8

Varity_R

0.19

gMVP

0.048

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.62

dbscSNV1_RF

Benign

0.45

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

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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