2-121530886-C-T

Position:

• chr2-121530886-C-T

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.196-561G>A variant causes a intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000367 in 692,792 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: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: CLASP1 NM_001395891.1 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.44

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=-0.22).
• BS2: High AC in GnomAd4 at 36 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	c.196-561G>A		intron_variant		ENST00000696935.1	NP_001382820.1
RNU4ATAC	NR_023343.1	n.7C>T		non_coding_transcript_exon_variant	1/1
CLASP1-AS1	XR_001739683.2	n.608+111C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLASP1	ENST00000696935.1	c.196-561G>A		intron_variant			NM_001395891.1	ENSP00000512981	A2
RNU4ATAC	ENST00000580972.1	n.6C>T		non_coding_transcript_exon_variant	1/1
CLASP1-AS1	ENST00000577914.1	n.354+111C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000386 AC: 50 AN: 129564 Hom.: 0 AF XY: 0.000410 AC XY: 29 AN XY: 70758

Gnomad AFR exome AF: 0.000164

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.000248

Gnomad EAS exome AF: 0.000192

Gnomad SAS exome AF: 0.000315

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000385

Gnomad OTH exome AF: 0.000503

GnomAD4 exome AF: 0.000403 AC: 218 AN: 540624 Hom.: 0 Cov.: 0 AF XY: 0.000415 AC XY: 121 AN XY: 291526

Gnomad4 AFR exome AF: 0.000257

Gnomad4 AMR exome AF: 0.000523

Gnomad4 ASJ exome AF: 0.000251

Gnomad4 EAS exome AF: 0.000314

Gnomad4 SAS exome AF: 0.000401

Gnomad4 FIN exome AF: 0.0000604

Gnomad4 NFE exome AF: 0.000454

Gnomad4 OTH exome AF: 0.000433

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74334

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000298

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 24, 2022

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 (rs764712132, gnomAD 0.07%). 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: 1366874). 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	-0.22
CADD	Benign	20
DANN	Benign	0.95

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: rs764712132; hg19: chr2-122288462;