Genetic Variant NM_014460.4:c.99G>C (chr22-41572064-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014460.4(CSDC2):c.99G>C(p.Arg33Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000822 in 1,363,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

CSDC2
NM_014460.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.00400

Variant links:

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]

CSDC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.023757517).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSDC2	NM_014460.4 link	c.99G>C	p.Arg33Ser	missense_variant	Exon 2 of 4	ENST00000306149.12	NP_055275.1	Q9Y534

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSDC2	ENST00000306149.12 link	c.99G>C	p.Arg33Ser	missense_variant	Exon 2 of 4	1	NM_014460.4	ENSP00000302485.7		Q9Y534
CSDC2	ENST00000460790.1 link	c.48G>C	p.Arg16Ser	missense_variant	Exon 1 of 3	3		ENSP00000417127.1		H7C4E7

Frequencies

GnomAD3 genomes

AF:

0.000408

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000131

AC:

AN:

53262

Hom.:

AF XY:

0.00

AC XY:

AN XY:

26538

show subpopulations

Gnomad AFR exome

AF:

0.000961

Gnomad AMR exome

AF:

0.000952

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

AF:

0.0000421

AC:

AN:

1210818

Hom.:

Cov.:

AF XY:

0.0000274

AC XY:

AN XY:

584174

show subpopulations

Gnomad4 AFR exome

AF:

0.00161

Gnomad4 AMR exome

AF:

0.000190

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000226

Gnomad4 NFE exome

AF:

0.00000405

Gnomad4 OTH exome

AF:

0.0000814

GnomAD4 genome

AF:

0.000401

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.00142

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000356

Hom.:

Bravo

AF:

0.000412

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000693

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 23, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.99G>C (p.R33S) alteration is located in exon 2 (coding exon 1) of the CSDC2 gene. This alteration results from a G to C substitution at nucleotide position 99, causing the arginine (R) at amino acid position 33 to be replaced by a serine (S). 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

Uncertain

0.40

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.037

T;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.0055

MetaRNN

Benign

0.024

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;.

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.67

N;N

REVEL

Uncertain

0.40

Sift

Benign

0.066

T;D

Sift4G

Benign

0.23

T;D

Polyphen

0.42

B;.

Vest4

0.51

MutPred

0.25

Loss of MoRF binding (P = 0.007);.;

MVP

0.38

MPC

0.67

ClinPred

0.031

GERP RS

0.072

Varity_R

0.11

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over