21-41905834-G-C

Variant names:

• chr21-41905834-G-C
• rs1244388047
• NM_015500.2:c.1322C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_015500.2(C2CD2):​c.1322C>G​(p.Ser441Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: C2CD2 NM_015500.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.64

Genes affected

C2CD2 (HGNC:1266): (C2 calcium dependent domain containing 2) Located in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity C2CD2_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C2CD2	NM_015500.2	c.1322C>G	p.Ser441Cys	missense_variant	Exon 11 of 14	ENST00000380486.4	NP_056315.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C2CD2	ENST00000380486.4	c.1322C>G	p.Ser441Cys	missense_variant	Exon 11 of 14	1	NM_015500.2	ENSP00000369853.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251272 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135834

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00000144 AC: 2 AN: 1390712 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 695880

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

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: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1322C>G (p.S441C) alteration is located in exon 11 (coding exon 11) of the C2CD2 gene. This alteration results from a C to G substitution at nucleotide position 1322, causing the serine (S) at amino acid position 441 to be replaced by a cysteine (C). 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	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Benign	0.22	.;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.87	T
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.082	T;T
Polyphen		0.15	.;B
Vest4		0.50
MutPred		0.16		.;Loss of phosphorylation at S441 (P = 0.029);
MVP		0.49
MPC		0.88
ClinPred		0.88	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.45

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

LitVar

Other links and lift over

dbSNP: rs1244388047; hg19: chr21-43325943;