1-35737382-A-G

Variant names:

• chr1-35737382-A-G
• NM_022111.4:c.3704T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022111.4(CLSPN):​c.3704T>C​(p.Leu1235Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CLSPN NM_022111.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0486919).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022111.4. 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
	CLSPN	NM_022111.4	MANE Select	c.3704T>C	p.Leu1235Pro	missense	Exon 23 of 25	NP_071394.2
	CLSPN	NM_001330490.2		c.3704T>C	p.Leu1235Pro	missense	Exon 23 of 25	NP_001317419.1	Q9HAW4-3
	CLSPN	NM_001190481.2		c.3512T>C	p.Leu1171Pro	missense	Exon 22 of 24	NP_001177410.1	Q9HAW4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLSPN	ENST00000318121.8	TSL:1 MANE Select	c.3704T>C	p.Leu1235Pro	missense	Exon 23 of 25	ENSP00000312995.3	Q9HAW4-1
	CLSPN	ENST00000251195.9	TSL:1	c.3704T>C	p.Leu1235Pro	missense	Exon 23 of 25	ENSP00000251195.5	Q9HAW4-3
	CLSPN	ENST00000520551.1	TSL:1	c.3545T>C	p.Leu1182Pro	missense	Exon 23 of 25	ENSP00000428848.1	E7ESG2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461782 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111944

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	Benign	0.051
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0032	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.6
PrimateAI	Benign	0.28	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.033
Sift	Benign	0.37	T
Sift4G	Benign	0.29	T
Polyphen		0.0020	B
Vest4		0.094
MutPred		0.27		Gain of relative solvent accessibility (P = 0.0098)
MVP		0.11
MPC		0.14
ClinPred		0.44	T
GERP RS		2.4
Varity_R		0.033
gMVP		0.16
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr1-36202983;