12-22457075-C-T

Variant names:

• chr12-22457075-C-T
• rs2135997084
• NM_001286176.2:c.2773G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001286176.2(C2CD5):​c.2773G>A​(p.Val925Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,612,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: C2CD5 NM_001286176.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.49
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27964035).

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.2773G>A	p.Val925Ile	missense	Exon 25 of 27	NP_001273105.1	Q86YS7-3
	C2CD5	NM_001385322.1		c.2965G>A	p.Val989Ile	missense	Exon 26 of 28	NP_001372251.1
	C2CD5	NM_001385323.1		c.2812G>A	p.Val938Ile	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.2773G>A	p.Val925Ile	missense	Exon 25 of 27	ENSP00000388756.1	Q86YS7-3
	C2CD5	ENST00000536386.5	TSL:1	c.2779G>A	p.Val927Ile	missense	Exon 26 of 28	ENSP00000439392.1	Q86YS7-4
	C2CD5	ENST00000396028.6	TSL:1	c.2746G>A	p.Val916Ile	missense	Exon 25 of 27	ENSP00000379345.2	Q86YS7-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

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

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460346 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726544

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111010

Other (OTH) AF: 0.00 AC: 0 AN: 60328

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74464

African (AFR) AF: 0.00 AC: 0 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2110

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	0.0074	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.055	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.14
Sift	Benign	0.43	T
Sift4G	Benign	0.30	T
Polyphen		0.96	P
Vest4		0.35
MutPred		0.29		Gain of catalytic residue at K876 (P = 0)
MVP		0.75
MPC		0.35
ClinPred		0.83	D
GERP RS		5.0
Varity_R		0.087
gMVP		0.55
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2135997084; hg19: chr12-22610009;