chr12-22472010-G-C

Position:

• chr12-22472010-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001286176.2(C2CD5):​c.2225C>G​(p.Ala742Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,457,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (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: 4.33

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17923597).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C2CD5	NM_001286176.2	c.2225C>G	p.Ala742Gly	missense_variant	19/27	ENST00000446597.6	NP_001273105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C2CD5	ENST00000446597.6	c.2225C>G	p.Ala742Gly	missense_variant	19/27	1	NM_001286176.2	ENSP00000388756.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457622 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 725252

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.2225C>G (p.A742G) alteration is located in exon 19 (coding exon 18) of the C2CD5 gene. This alteration results from a C to G substitution at nucleotide position 2225, causing the alanine (A) at amino acid position 742 to be replaced by a glycine (G). 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	0.086
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T;.;.;.;.;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D;.;D;D;D;D
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.18	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.55	N;N;.;.;N;.
MutationTaster	Benign	0.83	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.16	N;N;N;N;N;N
REVEL	Benign	0.097
Sift	Benign	0.23	T;T;T;T;T;T
Sift4G	Benign	0.45	T;T;T;T;T;T
Polyphen		0.0	B;.;.;B;.;.
Vest4		0.082
MutPred		0.29		Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);.;.;Loss of helix (P = 0.0444);.;
MVP		0.75
MPC		0.40
ClinPred		0.52	D
GERP RS		5.7
Varity_R		0.099
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs1591985831; hg19: chr12-22624944;