22-41572093-G-T

Variant names:

• chr22-41572093-G-T
• rs374172494
• NM_014460.4:c.128G>T

Variant summary

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

The NM_014460.4(CSDC2):​c.128G>T​(p.Arg43Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000829 in 1,206,296 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. R43W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: CSDC2 NM_014460.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• 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 2 ACMG points.

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

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.128G>T	p.Arg43Leu	missense	Exon 2 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.128G>T	p.Arg43Leu	missense	Exon 2 of 4	ENSP00000302485.7	Q9Y534
	CSDC2	ENST00000901851.1		c.128G>T	p.Arg43Leu	missense	Exon 3 of 5	ENSP00000571910.1
	CSDC2	ENST00000901852.1		c.128G>T	p.Arg43Leu	missense	Exon 2 of 4	ENSP00000571911.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.29e-7 AC: 1 AN: 1206296 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 581612

⚠️ 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: 25170

American (AMR) AF: 0.00 AC: 0 AN: 12950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16206

East Asian (EAS) AF: 0.0000336 AC: 1 AN: 29804

South Asian (SAS) AF: 0.00 AC: 0 AN: 41518

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4804

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 983028

Other (OTH) AF: 0.00 AC: 0 AN: 48670

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), 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	0.17
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.050	T
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0047	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L
PhyloP100		9.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.22
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.010	D
Polyphen		0.22	B
Vest4		0.58
MutPred		0.32		Gain of relative solvent accessibility (P = 0.0166)
MVP		0.48
MPC		0.68
ClinPred		0.89	D
GERP RS		4.9
PromoterAI		-0.0026	Neutral
Varity_R		0.23
gMVP		0.31
Mutation Taster		=67/33	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: rs374172494; hg19: chr22-41968097;