2-130341842-T-G

Position:

chr2-130341842-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_032357.4(CCDC115):c.214A>C(p.Ser72Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000819 in 977,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 26)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

CCDC115
NM_032357.4 missense, splice_region

Scores

Splicing: ADA: 0.04375

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.0470

Variant links:

Genes affected

CCDC115 (HGNC:28178): (coiled-coil domain containing 115) The protein encoded by this gene has been observed to localize to the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) and coat protein complex I (COPI) vesicles in some human cells. The encoded protein shares some homology with the yeast V-ATPase assembly factor Vma22p, and the orthologous protein in mouse promotes cell proliferation and suppresses cell death. Defects in this gene are a cause of congenital disorder of glycosylation, type IIo in humans. [provided by RefSeq, Mar 2016]

CCDC115 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.316415).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC115	NM_032357.4 linkuse as main transcript	c.214A>C	p.Ser72Arg	missense_variant, splice_region_variant	2/5	ENST00000259229.7	NP_115733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC115	ENST00000259229.7 linkuse as main transcript	c.214A>C	p.Ser72Arg	missense_variant, splice_region_variant	2/5	1	NM_032357.4	ENSP00000259229	P1	Q96NT0-1

Frequencies

GnomAD3 genomes

AF:

0.0000199

AC:

AN:

100626

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000391

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000165

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000421

AC:

AN:

237290

Hom.:

AF XY:

0.00

AC XY:

AN XY:

129180

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000298

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

876696

Hom.:

Cov.:

AF XY:

0.00000452

AC XY:

AN XY:

442316

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000166

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000199

AC:

AN:

100660

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

45418

show subpopulations

Gnomad4 AFR

AF:

0.0000390

Gnomad4 AMR

AF:

0.000165

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2021

The c.214A>C (p.S72R) alteration is located in exon 2 (coding exon 2) of the CCDC115 gene. This alteration results from a A to C substitution at nucleotide position 214, causing the serine (S) at amino acid position 72 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with CCDC115-related conditions. This variant is present in population databases (rs556226856, gnomAD 0.003%). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 72 of the CCDC115 protein (p.Ser72Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.050

T;T

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.072

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.081

MetaRNN

Benign

0.32

T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.3

L;.

MutationTaster

Benign

0.78

D;D;D

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.5

N;N

REVEL

Uncertain

0.34

Sift

Benign

0.21

T;T

Sift4G

Benign

0.68

T;T

Polyphen

0.021

B;B

Vest4

0.61

MutPred

0.46

Gain of solvent accessibility (P = 0.0171);.;

MVP

0.89

MPC

0.30

ClinPred

0.076

GERP RS

0.42

Varity_R

0.16

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.044

dbscSNV1_RF

Benign

0.50

SpliceAI score (max)

0.38

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.38

Position offset: 16

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