Genetic Variant CCDC175:p.Ser583Arg (chr14-59531787-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001164399.2(CCDC175):c.1747A>C(p.Ser583Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000595 in 1,344,736 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000059 ( 0 hom. )

Consequence

CCDC175
NM_001164399.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.94

Publications

0 publications found

Variant links:

Genes affected

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

CCDC175 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06475833).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC175	NM_001164399.2 link	c.1747A>C	p.Ser583Arg	missense_variant	Exon 14 of 20	ENST00000537690.7	NP_001157871.1	P0C221

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC175	ENST00000537690.7 link	c.1747A>C	p.Ser583Arg	missense_variant	Exon 14 of 20	5	NM_001164399.2	ENSP00000453940.1		P0C221
CCDC175	ENST00000281581.5 link	c.1747A>C	p.Ser583Arg	missense_variant	Exon 14 of 20	5		ENSP00000452964.1		A0A0A0MTQ8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

125748

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000365

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000595

AC:

AN:

1344736

Hom.:

Cov.:

AF XY:

0.00000301

AC XY:

AN XY:

664320

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29910

American (AMR)

AF:

0.00

AC:

AN:

29614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24452

East Asian (EAS)

AF:

0.00

AC:

AN:

35190

South Asian (SAS)

AF:

0.00

AC:

AN:

73598

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34816

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5578

European-Non Finnish (NFE)

AF:

0.00000569

AC:

AN:

1055016

Other (OTH)

AF:

0.0000354

AC:

AN:

56562

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 29, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1747A>C (p.S583R) alteration is located in exon 14 (coding exon 14) of the CCDC175 gene. This alteration results from a A to C substitution at nucleotide position 1747, causing the serine (S) at amino acid position 583 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

Benign

0.25

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.0070

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.0046

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.38

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.065

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

L;.

PhyloP100

-2.9

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.79

N;N

Sift

Benign

0.61

T;T

Sift4G

Benign

0.58

T;T

Vest4

0.10

MVP

0.014

ClinPred

0.054

GERP RS

-7.0

Varity_R

0.14

gMVP

0.042

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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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chr14-59531787-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over