chr2-121530884-A-G

Variant names:

• chr2-121530884-A-G
• rs533487249
• NM_001395891.1:c.196-559T>C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_001395891.1(CLASP1):​c.196-559T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 692,674 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: CLASP1 NM_001395891.1 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.769

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]

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]

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

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BS2: High AC in GnomAd4 at 32 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 rank	MANE	Protein	UniProt
CLASP1	NM_001395891.1	c.196-559T>C		intron_variant	Intron 2 of 40	ENST00000696935.1	NP_001382820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLASP1	ENST00000696935.1	c.196-559T>C		intron_variant	Intron 2 of 40		NM_001395891.1	ENSP00000512981.1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152082 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000232 AC: 30 AN: 129496 Hom.: 0 AF XY: 0.000198 AC XY: 14 AN XY: 70722

Gnomad AFR exome AF: 0.000164

Gnomad AMR exome AF: 0.000250

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000385

Gnomad SAS exome AF: 0.0000450

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000365

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000239 AC: 129 AN: 540474 Hom.: 1 Cov.: 0 AF XY: 0.000220 AC XY: 64 AN XY: 291478

Gnomad4 AFR exome AF: 0.0000643

Gnomad4 AMR exome AF: 0.000350

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000376

Gnomad4 SAS exome AF: 0.0000962

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000299

Gnomad4 OTH exome AF: 0.0000999

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74418

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000967

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000249

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (rs533487249, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with RNU4ATAC-related conditions. ClinVar contains an entry for this variant (Variation ID: 1045423). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs533487249; hg19: chr2-122288460;