Genetic Variant CCDC175:p.Arg693Gln (chr14-59521594-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001164399.2(CCDC175):c.2078G>A(p.Arg693Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,533,510 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 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. R693P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 27 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 20 hom. )

Consequence

CCDC175
NM_001164399.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.552

Publications

3 publications found

Variant links:

Genes affected

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

CCDC175 links:

ENSG00000258782 (HGNC:):

ENSG00000258782 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020184815).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0118 (1800/152230) while in subpopulation AFR AF = 0.0417 (1734/41538). AF 95% confidence interval is 0.0401. There are 27 homozygotes in GnomAd4. There are 854 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC175	NM_001164399.2 link	c.2078G>A	p.Arg693Gln	missense_variant	Exon 17 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.2078G>A	p.Arg693Gln	missense_variant	Exon 17 of 20	5	NM_001164399.2	ENSP00000453940.1	P0C221
CCDC175	ENST00000281581.5 link	c.2078G>A	p.Arg693Gln	missense_variant	Exon 17 of 20	5		ENSP00000452964.1	A0A0A0MTQ8
ENSG00000258782	ENST00000554253.1 link	n.239G>A		non_coding_transcript_exon_variant	Exon 2 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.0118

AC:

1800

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0419

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00958

GnomAD2 exomes

AF:

0.00284

AC:

414

AN:

145854

AF XY:

0.00204

show subpopulations

Gnomad AFR exome

AF:

0.0425

Gnomad AMR exome

AF:

0.00240

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000133

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.00113

AC:

1560

AN:

1381280

Hom.:

Cov.:

AF XY:

0.000978

AC XY:

667

AN XY:

681894

show subpopulations

African (AFR)

AF:

0.0399

AC:

1253

AN:

31392

American (AMR)

AF:

0.00258

AC:

AN:

35678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25150

East Asian (EAS)

AF:

0.00

AC:

AN:

35714

South Asian (SAS)

AF:

0.000164

AC:

AN:

79046

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35158

Middle Eastern (MID)

AF:

0.00105

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.0000400

AC:

AN:

1075530

Other (OTH)

AF:

0.00264

AC:

153

AN:

57924

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.427

Heterozygous variant carriers

126

188

251

314

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0118

AC:

1800

AN:

152230

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

854

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0417

AC:

1734

AN:

41538

American (AMR)

AF:

0.00248

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68000

Other (OTH)

AF:

0.00948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

168

253

337

421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00336

Hom.:

Bravo

AF:

0.0128

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0520

AC:

ESP6500EA

AF:

0.000314

AC:

ExAC

AF:

0.00498

AC:

119

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.0040

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.56

T;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.

PhyloP100

0.55

PrimateAI

Benign

0.21

PROVEAN

Benign

0.22

N;N

Sift

Benign

0.42

T;T

Sift4G

Benign

0.61

T;T

Vest4

0.062

MVP

0.014

ClinPred

0.0031

GERP RS

1.6

Varity_R

0.019

gMVP

0.027

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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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14-59521594-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over