Genetic Variant NM_001164399.2:c.1987T>A (chr14-59525290-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001164399.2(CCDC175):c.1987T>A(p.Leu663Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000759 in 1,448,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

CCDC175
NM_001164399.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.60

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10172245).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC175	NM_001164399.2 link	c.1987T>A	p.Leu663Ile	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.1987T>A	p.Leu663Ile	missense_variant	Exon 16 of 20	5	NM_001164399.2	ENSP00000453940.1	P0C221
CCDC175	ENST00000281581.5 link	c.1987T>A	p.Leu663Ile	missense_variant	Exon 16 of 20	5		ENSP00000452964.1	A0A0A0MTQ8
ENSG00000258782	ENST00000554253.1 link	n.148T>A		non_coding_transcript_exon_variant	Exon 1 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000380

AC:

AN:

78938

AF XY:

0.0000461

show subpopulations

Gnomad AFR exome

AF:

0.000220

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:

0.0000522

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000833

AC:

108

AN:

1296792

Hom.:

Cov.:

AF XY:

0.0000991

AC XY:

AN XY:

636004

show subpopulations

African (AFR)

AF:

0.0000376

AC:

AN:

26628

American (AMR)

AF:

0.00

AC:

AN:

17380

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21512

East Asian (EAS)

AF:

0.00

AC:

AN:

32570

South Asian (SAS)

AF:

0.00

AC:

AN:

64846

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32756

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4246

European-Non Finnish (NFE)

AF:

0.0000997

AC:

104

AN:

1042964

Other (OTH)

AF:

0.0000557

AC:

AN:

53890

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41410

American (AMR)

AF:

0.00

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2090

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1987T>A (p.L663I) alteration is located in exon 16 (coding exon 16) of the CCDC175 gene. This alteration results from a T to A substitution at nucleotide position 1987, causing the leucine (L) at amino acid position 663 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

0.17

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.012

T;T

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.66

T;T

M_CAP

Benign

0.045

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.

PhyloP100

1.6

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.75

N;N

Sift

Benign

0.11

T;T

Sift4G

Uncertain

0.039

D;D

Vest4

0.32

MVP

0.095

ClinPred

0.082

GERP RS

3.6

Varity_R

0.074

gMVP

0.047

Mutation Taster

=95/5

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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NM_001164399.2:c.1987T>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over