Genetic Variant CLSPN:p.Met1207Val (chr1-35738037-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022111.4(CLSPN):c.3619A>G(p.Met1207Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000015 in 1,335,644 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

CLSPN
NM_022111.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.61

Variant links:

Genes affected

CLSPN (HGNC:19715): (claspin) The product of this gene is an essential upstream regulator of checkpoint kinase 1 and triggers a checkpoint arrest of the cell cycle in response to replicative stress or DNA damage. The protein is also required for efficient DNA replication during a normal S phase. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

CLSPN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLSPN	NM_022111.4 link	c.3619A>G	p.Met1207Val	missense_variant	Exon 22 of 25	ENST00000318121.8	NP_071394.2	Q9HAW4-1
CLSPN	NM_001330490.2 link	c.3619A>G	p.Met1207Val	missense_variant	Exon 22 of 25		NP_001317419.1	Q9HAW4-3
CLSPN	NM_001190481.2 link	c.3427A>G	p.Met1143Val	missense_variant	Exon 21 of 24		NP_001177410.1	Q9HAW4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLSPN	ENST00000318121.8 link	c.3619A>G	p.Met1207Val	missense_variant	Exon 22 of 25	1	NM_022111.4	ENSP00000312995.3		Q9HAW4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000484

AC:

AN:

206686

Hom.:

AF XY:

0.00

AC XY:

AN XY:

113216

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000734

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:

0.00000150

AC:

AN:

1335644

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

660676

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000279

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.61e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3619A>G (p.M1207V) alteration is located in exon 22 (coding exon 22) of the CLSPN gene. This alteration results from a A to G substitution at nucleotide position 3619, causing the methionine (M) at amino acid position 1207 to be replaced by a valine (V). 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

0.36

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.043

.;T;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

D;D;D;D

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.65

D;D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.8

M;M;.;.

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.9

N;N;N;N

REVEL

Benign

0.19

Sift

Uncertain

0.028

D;D;T;T

Sift4G

Benign

0.10

T;D;D;T

Polyphen

0.99, 0.60

.;D;P;.

Vest4

0.77

MutPred

0.31

Loss of disorder (P = 0.0619);Loss of disorder (P = 0.0619);.;.;

MVP

0.47

MPC

0.41

ClinPred

0.67

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.39

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

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