3-33535337-G-A

Variant names:

• chr3-33535337-G-A
• rs750046209
• NM_001365631.1:c.3683C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_001365631.1(CLASP2):​c.3683C>T​(p.Ser1228Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CLASP2 NM_001365631.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12187445).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLASP2	NM_001365631.1	c.3683C>T	p.Ser1228Phe	missense_variant	Exon 34 of 39	ENST00000682230.1	NP_001352560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLASP2	ENST00000682230.1	c.3683C>T	p.Ser1228Phe	missense_variant	Exon 34 of 39		NM_001365631.1	ENSP00000507498.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249252 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135218

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461646 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3710C>T (p.S1237F) alteration is located in exon 35 (coding exon 35) of the CLASP2 gene. This alteration results from a C to T substitution at nucleotide position 3710, causing the serine (S) at amino acid position 1237 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	.;T;.;T;T;.
Eigen	Benign	0.051
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.12	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.1	N;N;.;D;N;.
REVEL	Benign	0.099
Sift	Benign	0.20	T;T;.;T;T;.
Sift4G	Benign	0.75	T;T;T;T;T;T
Polyphen		0.0	.;B;.;.;.;.
Vest4		0.25
MutPred		0.21		.;Loss of glycosylation at S1235 (P = 0.008);.;.;.;.;
MVP		0.25
MPC		0.79
ClinPred		0.23	T
GERP RS		5.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs750046209; hg19: chr3-33576829;