12-22469744-T-C

Variant names:

• chr12-22469744-T-C
• rs781195596
• NM_001286176.2:c.2498A>G

Variant summary

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

The NM_001286176.2(C2CD5):​c.2498A>G​(p.Asp833Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,454,192 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: C2CD5 NM_001286176.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.98

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

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=0.21350232).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C2CD5	NM_001286176.2	c.2498A>G	p.Asp833Gly	missense_variant	Exon 22 of 27	ENST00000446597.6	NP_001273105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C2CD5	ENST00000446597.6	c.2498A>G	p.Asp833Gly	missense_variant	Exon 22 of 27	1	NM_001286176.2	ENSP00000388756.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000818 AC: 2 AN: 244446 Hom.: 0 AF XY: 0.00000755 AC XY: 1 AN XY: 132444

Gnomad AFR exome AF: 0.0000639

Gnomad AMR exome AF: 0.0000301

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: 0.00000275 AC: 4 AN: 1454192 Hom.: 0 Cov.: 28 AF XY: 0.00000415 AC XY: 3 AN XY: 723398

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000456

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2498A>G (p.D833G) alteration is located in exon 22 (coding exon 21) of the C2CD5 gene. This alteration results from a A to G substitution at nucleotide position 2498, causing the aspartic acid (D) at amino acid position 833 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	0.23
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.063	T;.;.;.;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.21	T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.2	M;M;.;.;M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.14	T;T;T;T;T;T
Sift4G	Benign	0.20	T;T;T;T;T;T
Polyphen		0.46	P;.;.;D;.;.
Vest4		0.31
MutPred		0.21		Gain of catalytic residue at L830 (P = 0.0061);Gain of catalytic residue at L830 (P = 0.0061);.;.;Gain of catalytic residue at L830 (P = 0.0061);.;
MVP		0.72
MPC		0.57
ClinPred		0.33	T
GERP RS		4.9
Varity_R		0.22
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs781195596; hg19: chr12-22622678;