12-22469792-G-A

Variant names:

• chr12-22469792-G-A
• NM_001286176.2:c.2450C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001286176.2(C2CD5):​c.2450C>T​(p.Ser817Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000697 in 1,435,314 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: 7.0e-7 (0 hom.)
• Consequence: C2CD5 NM_001286176.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82

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 2 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity C2CD5_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23943529).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C2CD5	NM_001286176.2	c.2450C>T	p.Ser817Leu	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.2450C>T	p.Ser817Leu	missense_variant	Exon 22 of 27	1	NM_001286176.2	ENSP00000388756.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1435314 Hom.: 0 Cov.: 25 AF XY: 0.00000140 AC XY: 1 AN XY: 714350

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: 0.00

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2450C>T (p.S817L) alteration is located in exon 22 (coding exon 21) of the C2CD5 gene. This alteration results from a C to T substitution at nucleotide position 2450, causing the serine (S) at amino acid position 817 to be replaced by a leucine (L). 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	0.11
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.055	T;.;.;.;.;.
Eigen	Benign	0.051
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.24	T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.6	L;L;.;.;L;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.075	T;T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T;T
Polyphen		0.031	B;.;.;P;.;.
Vest4		0.49
MutPred		0.23		Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);.;.;Loss of relative solvent accessibility (P = 0.0186);.;
MVP		0.62
MPC		0.36
ClinPred		0.91	D
GERP RS		5.1
Varity_R		0.16
gMVP		0.36

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-22622726;