22-41573774-C-T

Variant names:

• chr22-41573774-C-T
• NM_014460.4:c.296C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014460.4(CSDC2):​c.296C>T​(p.Ser99Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,459,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CSDC2 NM_014460.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.84
• Publications: 0 publications found

Genes affected

CSDC2 (HGNC:30359): (cold shock domain containing C2) Predicted to enable mRNA 3'-UTR binding activity. Predicted to be involved in regulation of mRNA stability. Predicted to be located in nucleus. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014460.4. 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
	CSDC2	NM_014460.4	MANE Select	c.296C>T	p.Ser99Phe	missense	Exon 3 of 4	NP_055275.1	Q9Y534

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSDC2	ENST00000306149.12	TSL:1 MANE Select	c.296C>T	p.Ser99Phe	missense	Exon 3 of 4	ENSP00000302485.7	Q9Y534
	CSDC2	ENST00000901851.1		c.296C>T	p.Ser99Phe	missense	Exon 4 of 5	ENSP00000571910.1
	CSDC2	ENST00000901852.1		c.296C>T	p.Ser99Phe	missense	Exon 3 of 4	ENSP00000571911.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459828 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 6 AN XY: 726098

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1110694

Other (OTH) AF: 0.00 AC: 0 AN: 60292

GnomAD4 genome Cov.: 32

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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.8
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.82
Sift	Benign	0.069	T
Sift4G	Uncertain	0.049	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.75		Loss of disorder (P = 0.0514)
MVP		0.77
MPC		1.4
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.77
gMVP		0.63
Mutation Taster		=19/81	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

hg19: chr22-41969778;