12-22457135-C-T

Variant names:

• chr12-22457135-C-T
• rs375588532
• NM_001286176.2:c.2713G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001286176.2(C2CD5):​c.2713G>A​(p.Val905Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. V905A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: C2CD5 NM_001286176.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.296
• Publications: 0 publications found

Genes affected

C2CD5 (HGNC:29062): (C2 calcium dependent domain containing 5) Enables calcium ion binding activity and calcium-dependent phospholipid binding activity. Involved in cellular response to insulin stimulus; intracellular protein transmembrane transport; and positive regulation of transport. Located in several cellular components, including centriolar satellite; cytoplasmic vesicle membrane; and ruffle membrane. [provided by Alliance of Genome Resources, Apr 2022]

C2CD5-AS1 (HGNC:55961): (C2CD5 antisense RNA 1)

ACMG classification

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=0.03106594).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286176.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2CD5	NM_001286176.2	MANE Select	c.2713G>A	p.Val905Met	missense	Exon 25 of 27	NP_001273105.1	Q86YS7-3
	C2CD5	NM_001385322.1		c.2905G>A	p.Val969Met	missense	Exon 26 of 28	NP_001372251.1
	C2CD5	NM_001385323.1		c.2752G>A	p.Val918Met	missense	Exon 26 of 28	NP_001372252.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2CD5	ENST00000446597.6	TSL:1 MANE Select	c.2713G>A	p.Val905Met	missense	Exon 25 of 27	ENSP00000388756.1	Q86YS7-3
	C2CD5	ENST00000536386.5	TSL:1	c.2719G>A	p.Val907Met	missense	Exon 26 of 28	ENSP00000439392.1	Q86YS7-4
	C2CD5	ENST00000396028.6	TSL:1	c.2686G>A	p.Val896Met	missense	Exon 25 of 27	ENSP00000379345.2	Q86YS7-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451510 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 721822

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32870

American (AMR) AF: 0.00 AC: 0 AN: 42522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25846

East Asian (EAS) AF: 0.00 AC: 0 AN: 39180

South Asian (SAS) AF: 0.00 AC: 0 AN: 83882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108260

Other (OTH) AF: 0.00 AC: 0 AN: 59964

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.057
DANN	Benign	0.77
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.022	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.30
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.49	N
REVEL	Benign	0.043
Sift	Benign	0.40	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.21		Gain of catalytic residue at G857 (P = 0.0068)
MVP		0.19
MPC		0.40
ClinPred		0.064	T
GERP RS		-8.5
Varity_R		0.018
gMVP		0.25
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs375588532; hg19: chr12-22610069; COSMIC: COSV100448942; COSMIC: COSV100448942;