chr3-33535340-C-T

Variant names:

• chr3-33535340-C-T
• rs746484508
• NM_001365631.1:c.3680G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001365631.1(CLASP2):​c.3680G>A​(p.Arg1227His) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,634 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CLASP2 NM_001365631.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.92
• Publications: 0 publications found

Genes affected

CLASP2 (HGNC:17078): (cytoplasmic linker associated protein 2) Enables cytoskeletal protein binding activity; dystroglycan binding activity; and protein tyrosine kinase binding activity. Involved in several processes, including microtubule cytoskeleton organization; positive regulation of extracellular matrix organization; and regulation of supramolecular fiber organization. Located in several cellular components, including basal cortex; cortical microtubule plus-end; and ruffle membrane. Colocalizes with focal adhesion; kinetochore; and microtubule cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365631.1. 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
	CLASP2	NM_001365631.1	MANE Select	c.3680G>A	p.Arg1227His	missense	Exon 34 of 39	NP_001352560.1	A0A804HJG7
	CLASP2	NM_001365628.1		c.3767G>A	p.Arg1256His	missense	Exon 35 of 40	NP_001352557.1
	CLASP2	NM_001365629.1		c.3764G>A	p.Arg1255His	missense	Exon 35 of 40	NP_001352558.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLASP2	ENST00000682230.1	MANE Select	c.3680G>A	p.Arg1227His	missense	Exon 34 of 39	ENSP00000507498.1	A0A804HJG7
	CLASP2	ENST00000468888.6	TSL:5	c.3704G>A	p.Arg1235His	missense	Exon 34 of 39	ENSP00000419974.2	E7EW49
	CLASP2	ENST00000399362.8	TSL:5	c.3701G>A	p.Arg1234His	missense	Exon 34 of 39	ENSP00000382297.4	E7ERI8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249236 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461634 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727106

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

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

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111812

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000827 AC: 1

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	0.15
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.068	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.83	T
PhyloP100		6.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.12		Loss of methylation at R1234 (P = 0.1741)
MVP		0.47
MPC		1.5
ClinPred		1.0	D
GERP RS		5.2
PromoterAI		-0.0059	Neutral
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

dbSNP: rs746484508; hg19: chr3-33576832; COSMIC: COSV56295564; COSMIC: COSV56295564;