Genetic Variant CCDC74A:p.Leu78Arg (chr2-131528203-T-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001258306.3(CCDC74A):c.233T>G(p.Leu78Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000353 in 1,612,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

CCDC74A
NM_001258306.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.89

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC74A	NM_001258306.3 link	c.233T>G	p.Leu78Arg	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.233T>G	p.Leu78Arg	missense_variant	Exon 1 of 8	1	NM_001258306.3	ENSP00000387009.3		Q96AQ1-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000244

AC:

AN:

245696

Hom.:

AF XY:

0.0000224

AC XY:

AN XY:

133640

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

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:

0.0000365

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000370

AC:

AN:

1460718

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

726614

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000468

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.233T>G (p.L78R) alteration is located in exon 1 (coding exon 1) of the CCDC74A gene. This alteration results from a T to G substitution at nucleotide position 233, causing the leucine (L) at amino acid position 78 to be replaced by an arginine (R). 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

Pathogenic

0.87

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;T;.

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Uncertain

0.24

MutationAssessor

Pathogenic

3.0

M;.;M

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.2

D;.;D

REVEL

Uncertain

0.60

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.99

D;.;D

Vest4

0.64

MVP

0.83

MPC

2.9

ClinPred

0.94

GERP RS

2.8

Varity_R

0.92

gMVP

0.72

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