Genetic Variant CCDC175:p.Asp654Glu (chr14-59525315-A-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001164399.2(CCDC175):c.1962T>A(p.Asp654Glu) 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 benign outcome for this variant. 15/21 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. D654A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CCDC175
NM_001164399.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.56

Publications

0 publications found

Variant links:

Genes affected

CCDC175 (HGNC:19847): (coiled-coil domain containing 175)

CCDC175 links:

ENSG00000258782 (HGNC:):

ENSG00000258782 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04670492).

BP6

Variant 14-59525315-A-T is Benign according to our data. Variant chr14-59525315-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 3486448.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC175	NM_001164399.2 link	c.1962T>A	p.Asp654Glu	missense_variant	Exon 16 of 20	ENST00000537690.7	NP_001157871.1	P0C221

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CCDC175	ENST00000537690.7 link	c.1962T>A	p.Asp654Glu	missense_variant	Exon 16 of 20	5	NM_001164399.2	ENSP00000453940.1	P0C221
CCDC175	ENST00000281581.5 link	c.1962T>A	p.Asp654Glu	missense_variant	Exon 16 of 20	5		ENSP00000452964.1	A0A0A0MTQ8
ENSG00000258782	ENST00000554253.1 link	n.123T>A		non_coding_transcript_exon_variant	Exon 1 of 6	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1309146

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

643804

African (AFR)

AF:

0.00

AC:

AN:

26820

American (AMR)

AF:

0.00

AC:

AN:

18420

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22336

East Asian (EAS)

AF:

0.00

AC:

AN:

32680

South Asian (SAS)

AF:

0.00

AC:

AN:

66798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33714

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4912

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1048940

Other (OTH)

AF:

0.00

AC:

AN:

54526

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Oct 06, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.0030

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.0043

T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0053

LIST_S2

Benign

0.42

T;T

M_CAP

Benign

0.0078

MetaRNN

Benign

0.047

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.14

N;.

PhyloP100

-1.6

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.010

N;N

Sift

Benign

0.71

T;T

Sift4G

Benign

1.0

T;T

Vest4

0.043

MVP

0.014

ClinPred

0.037

GERP RS

-9.6

Varity_R

0.034

gMVP

0.019

Mutation Taster

=98/2

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over