2-121363225-C-T

Variant names:

• chr2-121363225-C-T
• NM_001395891.1:c.4216G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001395891.1(CLASP1):​c.4216G>A​(p.Ala1406Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,588 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CLASP1 NM_001395891.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.59
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.4216G>A	p.Ala1406Thr	missense	Exon 38 of 41	NP_001382820.1	A0A8V8TLP7
	CLASP1	NM_015282.3		c.4153G>A	p.Ala1385Thr	missense	Exon 37 of 40	NP_056097.1	Q7Z460-1
	CLASP1	NM_001378003.1		c.4057G>A	p.Ala1353Thr	missense	Exon 36 of 39	NP_001364932.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLASP1	ENST00000696935.1	MANE Select	c.4216G>A	p.Ala1406Thr	missense	Exon 38 of 41	ENSP00000512981.1	A0A8V8TLP7
	CLASP1	ENST00000263710.8	TSL:5	c.4153G>A	p.Ala1385Thr	missense	Exon 37 of 40	ENSP00000263710.4	Q7Z460-1
	CLASP1	ENST00000961911.1		c.4096G>A	p.Ala1366Thr	missense	Exon 37 of 40	ENSP00000631970.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461588 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727070

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111838

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 33

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	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.092	T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.6
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.31
Sift	Benign	0.26	T
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.67
MVP		0.78
MPC		1.2
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.15
gMVP		0.50
Mutation Taster		=44/56	disease causing

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

Other links and lift over

hg19: chr2-122120801; COSMIC: COSV55318031; COSMIC: COSV55318031;