NM_015500.2:c.1876A>C

Variant names:

• chr21-41889339-T-G
• rs2064720927
• NM_015500.2:c.1876A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015500.2(C2CD2):​c.1876A>C​(p.Ile626Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000027 (0 hom.)
• Consequence: C2CD2 NM_015500.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.096126765).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015500.2. 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
	C2CD2	NM_015500.2	MANE Select	c.1876A>C	p.Ile626Leu	missense	Exon 14 of 14	NP_056315.1	Q9Y426-1
	C2CD2	NM_199050.3		c.1411A>C	p.Ile471Leu	missense	Exon 13 of 13	NP_950251.1	Q9Y426-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2CD2	ENST00000380486.4	TSL:1 MANE Select	c.1876A>C	p.Ile626Leu	missense	Exon 14 of 14	ENSP00000369853.3	Q9Y426-1
	C2CD2	ENST00000329623.11	TSL:1	c.1411A>C	p.Ile471Leu	missense	Exon 13 of 13	ENSP00000329302.7	Q9Y426-2
	C2CD2	ENST00000449165.5	TSL:1	c.331A>C	p.Ile111Leu	missense	Exon 3 of 3	ENSP00000388704.1	H7BZB0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460518 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726616

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44670

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111054

Other (OTH) AF: 0.00 AC: 0 AN: 60338

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.093
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.72
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.84
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.065
Sift	Benign	0.39	T
Sift4G	Benign	0.79	T
Polyphen		0.0060	B
Vest4		0.15
MutPred		0.38		Loss of methylation at K629 (P = 0.052)
MVP		0.20
MPC		0.26
ClinPred		0.20	T
GERP RS		-1.9
Varity_R		0.052
gMVP		0.079
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs2064720927; hg19: chr21-43309448;