NM_032357.4:c.304C>T

Variant names:

• chr2-130341034-G-A
• rs149024810
• NM_032357.4:c.304C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032357.4(CCDC115):​c.304C>T​(p.Arg102Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000243 in 1,604,294 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: CCDC115 NM_032357.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC115	NM_032357.4	c.304C>T	p.Arg102Trp	missense_variant	Exon 4 of 5	ENST00000259229.7	NP_115733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC115	ENST00000259229.7	c.304C>T	p.Arg102Trp	missense_variant	Exon 4 of 5	1	NM_032357.4	ENSP00000259229.2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000341 AC: 8 AN: 234798 Hom.: 0 AF XY: 0.0000394 AC XY: 5 AN XY: 127056

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 SAS exome AF: 0.0000692

Gnomad FIN exome AF: 0.0000489

Gnomad NFE exome AF: 0.0000473

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000234 AC: 34 AN: 1452102 Hom.: 0 Cov.: 31 AF XY: 0.0000208 AC XY: 15 AN XY: 721808

Gnomad4 AFR exome AF: 0.0000603

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000236

Gnomad4 FIN exome AF: 0.0000379

Gnomad4 NFE exome AF: 0.0000235

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000923 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 102 of the CCDC115 protein (p.Arg102Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CCDC115-related conditions. ClinVar contains an entry for this variant (Variation ID: 1393799). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.52
MVP		0.98
MPC		0.93
ClinPred		0.93	D
GERP RS		3.6
Varity_R		0.56
gMVP		0.72

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

LitVar

Other links and lift over

dbSNP: rs149024810; hg19: chr2-131098607;