Genetic Variant CCDC74A:p.Thr17Ile (chr2-131528020-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001258306.3(CCDC74A):c.50C>T(p.Thr17Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000169 in 1,483,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

CCDC74A
NM_001258306.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.337

Variant links:

Genes affected

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

CCDC74A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.017751455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC74A	NM_001258306.3 link	c.50C>T	p.Thr17Ile	missense_variant	Exon 1 of 8	ENST00000409856.8	NP_001245235.1	Q96AQ1-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC74A	ENST00000409856.8 link	c.50C>T	p.Thr17Ile	missense_variant	Exon 1 of 8	1	NM_001258306.3	ENSP00000387009.3		Q96AQ1-2

Frequencies

GnomAD3 genomes

AF:

0.0000922

AC:

AN:

151818

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000417

AC:

AN:

95872

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

50894

show subpopulations

Gnomad AFR exome

AF:

0.000566

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000826

AC:

AN:

1331430

Hom.:

Cov.:

AF XY:

0.00000768

AC XY:

AN XY:

650872

show subpopulations

Gnomad4 AFR exome

AF:

0.000306

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000148

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000182

GnomAD4 genome

AF:

0.0000922

AC:

AN:

151818

Hom.:

Cov.:

AF XY:

0.0000944

AC XY:

AN XY:

74138

show subpopulations

Gnomad4 AFR

AF:

0.000314

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.0000365

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 27, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.50C>T (p.T17I) alteration is located in exon 1 (coding exon 1) of the CCDC74A gene. This alteration results from a C to T substitution at nucleotide position 50, causing the threonine (T) at amino acid position 17 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

4.0

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0025

T;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.65

T;T;T

M_CAP

Benign

0.0097

MetaRNN

Benign

0.018

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.26

N;.;N

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.0

N;.;N

REVEL

Benign

0.023

Sift

Benign

0.16

T;.;D

Sift4G

Benign

0.11

T;T;T

Polyphen

0.0030

B;.;B

Vest4

0.074

MutPred

0.22

Loss of phosphorylation at T17 (P = 0.0013);Loss of phosphorylation at T17 (P = 0.0013);Loss of phosphorylation at T17 (P = 0.0013);

MVP

0.040

MPC

1.7

ClinPred

0.025

GERP RS

0.19

Varity_R

0.052

gMVP

0.093

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over