2-121367797-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BA1

The NM_001395891.1(CLASP1):c.3740C>A(p.Thr1247Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00371 in 1,613,780 control chromosomes in the GnomAD database, including 267 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0072 (44 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (223 hom.)
• Consequence: CLASP1 NM_001395891.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.28

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CLASP1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0016407967).
• BP6: Variant 2-121367797-G-T is Benign according to our data. Variant chr2-121367797-G-T is described in ClinVar as [Benign]. Clinvar id is 3037345.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0593 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLASP1	NM_001395891.1	c.3740C>A	p.Thr1247Asn	missense_variant	36/41	ENST00000696935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLASP1	ENST00000696935.1	c.3740C>A	p.Thr1247Asn	missense_variant	36/41		NM_001395891.1	A2

Frequencies

GnomAD3 genomes AF: 0.00724 AC: 1102 AN: 152208 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0625

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0104

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.0142 AC: 3521 AN: 248660 Hom.: 165 AF XY: 0.0106 AC XY: 1430 AN XY: 134982

Gnomad AFR exome AF: 0.000971

Gnomad AMR exome AF: 0.0916

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.0149

Gnomad SAS exome AF: 0.000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.00878

GnomAD4 exome AF: 0.00334 AC: 4880 AN: 1461454 Hom.: 223 Cov.: 32 AF XY: 0.00285 AC XY: 2074 AN XY: 727028

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.0908

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.0117

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.00381

GnomAD4 genome AF: 0.00725 AC: 1104 AN: 152326 Hom.: 44 Cov.: 32 AF XY: 0.00798 AC XY: 594 AN XY: 74476

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.0625

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0104

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00143 Hom.: 11

Bravo AF: 0.0122

ESP6500AA AF: 0.000767 AC: 3

ESP6500EA AF: 0.000241 AC: 2

ExAC AF: 0.0104 AC: 1252

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CLASP1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	21
Dann	Benign	0.51
DEOGEN2	Benign	0.030	T;.;.;T;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.069
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.0016	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;.;.;L;.;.
MutationTaster	Benign	0.65	D;D;D;D;D;D;D
PrimateAI	Benign	0.42	T
Polyphen		0.15	B;.;.;B;.;.
Vest4		0.31, 0.40, 0.30, 0.41
MPC		0.46
ClinPred		0.022	T
GERP RS		5.1
Varity_R		0.12
gMVP		0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs144957722; hg19: chr2-122125373;