rs35490896

Positions:

• chr1-35736984-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022111.4(CLSPN):​c.3839C>T​(p.Ser1280Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.06 in 1,613,982 control chromosomes in the GnomAD database, including 3,175 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.064 (368 hom., cov: 32)
  • Exomes 𝑓: 0.060 (2807 hom.)
• Consequence: CLSPN NM_022111.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.43

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017231405).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLSPN	NM_022111.4	c.3839C>T	p.Ser1280Leu	missense_variant	24/25	ENST00000318121.8
CLSPN	NM_001330490.2	c.3839C>T	p.Ser1280Leu	missense_variant	24/25
CLSPN	NM_001190481.2	c.3647C>T	p.Ser1216Leu	missense_variant	23/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLSPN	ENST00000318121.8	c.3839C>T	p.Ser1280Leu	missense_variant	24/25	1	NM_022111.4	P2

Frequencies

GnomAD3 genomes AF: 0.0642 AC: 9764 AN: 152118 Hom.: 369 Cov.: 32

Gnomad AFR AF: 0.0856

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0477

Gnomad ASJ AF: 0.0939

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0653

Gnomad FIN AF: 0.0464

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0618

Gnomad OTH AF: 0.0635

GnomAD3 exomes AF: 0.0553 AC: 13892 AN: 251364 Hom.: 443 AF XY: 0.0567 AC XY: 7697 AN XY: 135848

Gnomad AFR exome AF: 0.0885

Gnomad AMR exome AF: 0.0350

Gnomad ASJ exome AF: 0.0872

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.0669

Gnomad FIN exome AF: 0.0462

Gnomad NFE exome AF: 0.0611

Gnomad OTH exome AF: 0.0585

GnomAD4 exome AF: 0.0595 AC: 87005 AN: 1461746 Hom.: 2807 Cov.: 31 AF XY: 0.0600 AC XY: 43646 AN XY: 727166

Gnomad4 AFR exome AF: 0.0860

Gnomad4 AMR exome AF: 0.0362

Gnomad4 ASJ exome AF: 0.0894

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0683

Gnomad4 FIN exome AF: 0.0455

Gnomad4 NFE exome AF: 0.0608

Gnomad4 OTH exome AF: 0.0626

GnomAD4 genome AF: 0.0643 AC: 9782 AN: 152236 Hom.: 368 Cov.: 32 AF XY: 0.0634 AC XY: 4723 AN XY: 74438

Gnomad4 AFR AF: 0.0857

Gnomad4 AMR AF: 0.0477

Gnomad4 ASJ AF: 0.0939

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.0660

Gnomad4 FIN AF: 0.0464

Gnomad4 NFE AF: 0.0617

Gnomad4 OTH AF: 0.0629

Alfa AF: 0.0618 Hom.: 498

Bravo AF: 0.0660

TwinsUK AF: 0.0636 AC: 236

ALSPAC AF: 0.0550 AC: 212

ESP6500AA AF: 0.0822 AC: 362

ESP6500EA AF: 0.0649 AC: 558

ExAC AF: 0.0563 AC: 6830

Asia WGS AF: 0.0230 AC: 81 AN: 3478

EpiCase AF: 0.0693

EpiControl AF: 0.0639

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Benign	-0.11
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D;D
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;M;.;.
MutationTaster	Benign	0.83	N;N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Benign	0.086
Sift	Benign	0.043	D;D;D;D
Sift4G	Uncertain	0.054	T;T;T;T
Polyphen		0.0040, 0.0070	.;B;B;.
Vest4		0.088
MPC		0.090
ClinPred		0.030	T
GERP RS		4.3
Varity_R		0.16
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs35490896; hg19: chr1-36202585;