2-121530831-C-A

Variant names:

• chr2-121530831-C-A
• rs72969386
• NM_001395891.1:c.196-506G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001395891.1(CLASP1):​c.196-506G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000196 in 509,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: CLASP1 NM_001395891.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.26
• Publications: 0 publications found

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

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 Gene-Disease associations (from GenCC):

• microcephalic osteodysplastic primordial dwarfism type I

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• RNU4ATAC spectrum disorder

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Broad Center for Mendelian Genomics, Ambry Genetics, ClinGen
• Roifman syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina
• Lowry-Wood syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395891.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLASP1	NM_001395891.1	MANE Select	c.196-506G>T		intron	N/A	NP_001382820.1	A0A8V8TLP7
	CLASP1	NM_015282.3		c.196-506G>T		intron	N/A	NP_056097.1	Q7Z460-1
	CLASP1	NM_001378003.1		c.196-506G>T		intron	N/A	NP_001364932.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLASP1	ENST00000696935.1	MANE Select	c.196-506G>T		intron	N/A	ENSP00000512981.1	A0A8V8TLP7
	CLASP1	ENST00000263710.8	TSL:5	c.196-506G>T		intron	N/A	ENSP00000263710.4	Q7Z460-1
	CLASP1	ENST00000961911.1		c.196-506G>T		intron	N/A	ENSP00000631970.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000196 AC: 1 AN: 509026 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 271682

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 14422

American (AMR) AF: 0.00 AC: 0 AN: 31030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18786

East Asian (EAS) AF: 0.00 AC: 0 AN: 31368

South Asian (SAS) AF: 0.00 AC: 0 AN: 59588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2286

European-Non Finnish (NFE) AF: 0.00000344 AC: 1 AN: 290694

Other (OTH) AF: 0.00 AC: 0 AN: 28348

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.014
DANN	Benign	0.52
PhyloP100		-4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs72969386; hg19: chr2-122288407;