2-121530887-C-T

Position:

chr2-121530887-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP5BP4BS2_Supporting

The NM_001395891.1(CLASP1):c.196-562G>A variant causes a intron change. The variant allele was found at a frequency of 0.000426 in 692,974 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

CLASP1
NM_001395891.1 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2

Conservation

PhyloP100: 5.74

Variant links:

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 links:

RNU4ATAC (HGNC:34016): (RNA, U4atac small nuclear) The small nuclear RNA (snRNA) encoded by this gene is part of the U12-dependent minor spliceosome complex. In addition to the encoded RNA, this ribonucleoprotein complex consists of U11, U12, U5, and U6atac snRNAs. The U12-dependent spliceosome acts on approximately 700 specific introns in the human genome. Defects in this gene are a cause of microcephalic osteodysplastic primordial dwarfism type 1 (MOPD). [provided by RefSeq, Jul 2011]

RNU4ATAC links:

CLASP1-AS1 (HGNC:55328): (CLASP1 antisense RNA 1)

CLASP1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP5

Variant 2-121530887-C-T is Pathogenic according to our data. Variant chr2-121530887-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218086.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=3}. Variant chr2-121530887-C-T is described in Lovd as [Pathogenic]. Variant chr2-121530887-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.22). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAd4 at 60 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLASP1	NM_001395891.1 link	c.196-562G>A		intron_variant		ENST00000696935.1	NP_001382820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLASP1	ENST00000696935.1 link	c.196-562G>A		intron_variant			NM_001395891.1	ENSP00000512981.1		A0A8V8TLP7

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000386

AC:

AN:

129556

Hom.:

AF XY:

0.000410

AC XY:

AN XY:

70760

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000332

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000385

Gnomad SAS exome

AF:

0.000539

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000486

Gnomad OTH exome

AF:

0.000504

GnomAD4 exome

AF:

0.000435

AC:

235

AN:

540682

Hom.:

Cov.:

AF XY:

0.000453

AC XY:

132

AN XY:

291570

show subpopulations

Gnomad4 AFR exome

AF:

0.000128

Gnomad4 AMR exome

AF:

0.000465

Gnomad4 ASJ exome

AF:

0.0000502

Gnomad4 EAS exome

AF:

0.000314

Gnomad4 SAS exome

AF:

0.000529

Gnomad4 FIN exome

AF:

0.0000906

Gnomad4 NFE exome

AF:

0.000527

Gnomad4 OTH exome

AF:

0.000167

GnomAD4 genome

AF:

0.000394

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000171

Hom.:

Bravo

AF:

0.000408

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 30, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This variant occurs in the RNU4ATAC gene, which encodes an RNA molecule that does not result in a protein product. This variant is present in population databases (rs370715569, gnomAD 0.05%). This variant has been observed in individual(s) with clinical features of RNU4ATAC-related conditions (PMID: 26522830; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 218086). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Functional studies have shown that this variant disrupts ncRNA function (PMID: 32628740). For these reasons, this variant has been classified as Pathogenic. -

Roifman syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 02, 2015

- -

RNU4ATAC-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 18, 2023

The RNU4ATAC n.8C>T is a noncoding alteration. This variant has been reported in the compound heterozygous state in an individual with Roifman syndrome (Subject 6, Kindred K4, Merico et al. 2015. PubMed ID: 26522830). This variant is located in an element of major importance for splicing and is classified as a Roifman syndrome causal variant (Figure 3, Merico et al. 2015. PubMed ID: 26522830). A different substitution affecting the same nucleotide (n.8C>A) has been reported in the compound heterozygous state in an individual with Lowry-Wood syndrome (Shelihan et al. 2018. PubMed ID: 30368667). This variant is reported in 0.054% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-122288463-C-T). This variant is interpreted as likely pathogenic. -

Spondyloepiphyseal dysplasia congenita

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Mar 04, 2020

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 01, 2022

Variant summary: RNU4ATAC n.8C>T alters a nucleotide in the non-coding RNA and located in Stem II region (n.3-n.19, element of major importance for splicing; Merico_2015) of RNU4ATAC. Additionally, Stem II, which base pair the U6atac, required to form the catalytically active minor spliceosome (PMID: 29263834). The variant allele was found at a frequency of 0.00039 in 129556 control chromosomes (gnomAD). n.8C>T has been reported in the literature in at least one compound heterozygous individual affected with Roifman Syndrome (Merico_2015) and one individual with RNU4ATAC-related conditions reported in one ClinVar lab. These data indicate that the variant may be associated with disease. At least one functional study reports this variant results in reducing splicing efficiency in transfected cells (Benoit-Pilven_2020). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely pathogenic (n=3) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Craniosynostosis syndrome;C0349588:Short stature;C0878544:Cardiomyopathy;C4022738:Neurodevelopmental delay;C4551563:Microcephaly

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Apr 20, 2021

ACMG classification criteria: PS3 supporting, PM3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.96

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over