21-41905834-G-T

Variant names:

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

Variant summary

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

The NM_015500.2(C2CD2):​c.1322C>A​(p.Ser441Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000216 in 1,390,708 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S441C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: C2CD2 NM_015500.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.64
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1322C>A	p.Ser441Tyr	missense	Exon 11 of 14	NP_056315.1	Q9Y426-1
	C2CD2	NM_199050.3		c.857C>A	p.Ser286Tyr	missense	Exon 10 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.1322C>A	p.Ser441Tyr	missense	Exon 11 of 14	ENSP00000369853.3	Q9Y426-1
	C2CD2	ENST00000329623.11	TSL:1	c.857C>A	p.Ser286Tyr	missense	Exon 10 of 13	ENSP00000329302.7	Q9Y426-2
	C2CD2	ENST00000482186.5	TSL:1	n.1322C>A		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1390708 Hom.: 0 Cov.: 24 AF XY: 0.00000144 AC XY: 1 AN XY: 695878

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32086

American (AMR) AF: 0.00 AC: 0 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25728

East Asian (EAS) AF: 0.00 AC: 0 AN: 39312

South Asian (SAS) AF: 0.00 AC: 0 AN: 84860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 0.00000286 AC: 3 AN: 1047222

Other (OTH) AF: 0.00 AC: 0 AN: 57892

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0160444), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.71	T
PhyloP100		6.6
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.22		Gain of catalytic residue at S441 (P = 0.0276)
MVP		0.55
MPC		1.0
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.48
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs1244388047; hg19: chr21-43325943;