3-33538798-A-C

Variant names:

• chr3-33538798-A-C
• NM_001365631.1:c.3549T>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001365631.1(CLASP2):​c.3549T>G​(p.Asp1183Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,429,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/17 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: 7.0e-7 (0 hom.)
• Consequence: CLASP2 NM_001365631.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0550

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.035373777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLASP2	NM_001365631.1	c.3549T>G	p.Asp1183Glu	missense_variant	Exon 33 of 39	ENST00000682230.1	NP_001352560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLASP2	ENST00000682230.1	c.3549T>G	p.Asp1183Glu	missense_variant	Exon 33 of 39		NM_001365631.1	ENSP00000507498.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1429858 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 709750

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3576T>G (p.D1192E) alteration is located in exon 34 (coding exon 34) of the CLASP2 gene. This alteration results from a T to G substitution at nucleotide position 3576, causing the aspartic acid (D) at amino acid position 1192 to be replaced by a glutamic acid (E). 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	0.12
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	9.0
DANN	Benign	0.91
DEOGEN2	Benign	0.0051	.;T;.;T;T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.79	T;T;T;T;T;T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.035	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.55	N;N;.;N;N;.
REVEL	Benign	0.043
Sift	Benign	0.25	T;T;.;T;T;.
Sift4G	Benign	0.37	T;T;T;T;T;T
Polyphen		0.0	.;B;.;.;.;.
Vest4		0.099
MutPred		0.092		.;Gain of methylation at K1188 (P = 0.0714);.;.;.;.;
MVP		0.34
MPC		0.42
ClinPred		0.082	T
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-33580290;