2-121367762-G-C

Variant names:

• chr2-121367762-G-C
• rs755382948
• NM_001395891.1:c.3775C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001395891.1(CLASP1):​c.3775C>G​(p.Arg1259Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R1259W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLASP1 NM_001395891.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• Publications: 1 publications found

Genes affected

CLASP1 (HGNC:17088): (cytoplasmic linker associated protein 1) CLASPs, such as CLASP1, are nonmotor microtubule-associated proteins that interact with CLIPs (e.g., CLIP170; MIM 179838). CLASP1 is involved in the regulation of microtubule dynamics at the kinetochore and throughout the spindle (Maiato et al., 2003 [PubMed 12837247]).[supplied by OMIM, Mar 2008]

CLASP1 Gene-Disease associations (from GenCC):

• focal epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34373298).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395891.1. 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
	CLASP1	NM_001395891.1	MANE Select	c.3775C>G	p.Arg1259Gly	missense	Exon 36 of 41	NP_001382820.1	A0A8V8TLP7
	CLASP1	NM_015282.3		c.3712C>G	p.Arg1238Gly	missense	Exon 35 of 40	NP_056097.1	Q7Z460-1
	CLASP1	NM_001378003.1		c.3616C>G	p.Arg1206Gly	missense	Exon 34 of 39	NP_001364932.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLASP1	ENST00000696935.1	MANE Select	c.3775C>G	p.Arg1259Gly	missense	Exon 36 of 41	ENSP00000512981.1	A0A8V8TLP7
	CLASP1	ENST00000263710.8	TSL:5	c.3712C>G	p.Arg1238Gly	missense	Exon 35 of 40	ENSP00000263710.4	Q7Z460-1
	CLASP1	ENST00000961911.1		c.3655C>G	p.Arg1219Gly	missense	Exon 35 of 40	ENSP00000631970.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.28
Sift	Benign	0.14	T
Sift4G	Benign	0.082	T
Polyphen		1.0	D
Vest4		0.83
MutPred		0.29		Loss of methylation at R1238 (P = 0.035)
MVP		0.57
MPC		1.4
ClinPred		0.98	D
GERP RS		0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.30
gMVP		0.57
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs755382948; hg19: chr2-122125338;