chr2-121530930-G-A

Variant names:

• chr2-121530930-G-A
• rs188343279
• NM_001395891.1:c.196-605C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 12P and 2B. PS3 PP5_Very_Strong BP4 BS2_Supporting

The NM_001395891.1(CLASP1):​c.196-605C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000485 in 700,358 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003934281: The most pronounced variant effect results in <10% of normal activity (He_2012)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: CLASP1 NM_001395891.1 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21
• Conservation: PhyloP100: 2.51
• Publications: 9 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]

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

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003934281: The most pronounced variant effect results in <10% of normal activity (He_2012).; SCV002070508: Functional studies have also demonstrated that this sequence change reduced U12-dependent splicing activity by 90% compared to wildtype. PMID:21474760; SCV002243422: Functional studies have shown that this variant disrupts ncRNA function (PMID: 21474760).; SCV005871428: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV004115105: This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with RNU4ATAC-related disorders, and functional studies support its pathogenicity (He et al. 2011. PubMed ID: 21474760; Abdel-Salam et al. 2013. PubMed ID: 23794361; Merico et al. 2015. PubMed ID: 26522830; Farach et al. 2017. PubMed ID: 29265708; Benoit-Pilven et al. 2020. PubMed ID: 32628740).; SCV006583542: "Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product." PMID: 21474760; SCV007096864: Functional assays demonstrate this variant results in defective U12-dependant splicing, with dramatically reduced activity of spliceosomal function compared to wild type (PMID: 21474760).
• PP5: Variant 2-121530930-G-A is Pathogenic according to our data. Variant chr2-121530930-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 30178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd4 at 69 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.196-605C>T		intron	N/A	NP_001382820.1	A0A8V8TLP7
	RNU4ATAC	NR_023343.3	MANE Select	n.51G>A		non_coding_transcript_exon	Exon 1 of 1
	CLASP1	NM_015282.3		c.196-605C>T		intron	N/A	NP_056097.1	Q7Z460-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLASP1	ENST00000696935.1	MANE Select	c.196-605C>T		intron	N/A	ENSP00000512981.1	A0A8V8TLP7
	RNU4ATAC	ENST00000580972.2	TSL:6 MANE Select	n.51G>A		non_coding_transcript_exon	Exon 1 of 1
	CLASP1	ENST00000263710.8	TSL:5	c.196-605C>T		intron	N/A	ENSP00000263710.4	Q7Z460-1

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000429 AC: 56 AN: 130510 AF XY: 0.000407

Gnomad AFR exome AF: 0.000164

Gnomad AMR exome AF: 0.000575

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000383

Gnomad FIN exome AF: 0.000556

Gnomad NFE exome AF: 0.000402

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.000494 AC: 271 AN: 548072 Hom.: 0 Cov.: 0 AF XY: 0.000522 AC XY: 155 AN XY: 296768

African (AFR) AF: 0.000191 AC: 3 AN: 15734

American (AMR) AF: 0.000519 AC: 18 AN: 34708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20026

East Asian (EAS) AF: 0.000592 AC: 19 AN: 32108

South Asian (SAS) AF: 0.000686 AC: 43 AN: 62682

European-Finnish (FIN) AF: 0.000211 AC: 7 AN: 33196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2444

European-Non Finnish (NFE) AF: 0.000534 AC: 169 AN: 316762

Other (OTH) AF: 0.000395 AC: 12 AN: 30412

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.000457 AC XY: 34 AN XY: 74464

African (AFR) AF: 0.000289 AC: 12 AN: 41556

American (AMR) AF: 0.000261 AC: 4 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68030

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000216 Hom.: 0

Bravo AF: 0.000536

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
4	-	-	Osteodysplastic primordial dwarfism, type 1 (4)
4	-	-	Roifman syndrome (4)
2	-	-	Lowry-Wood syndrome;C1846059:Roifman syndrome;C1859452:Osteodysplastic primordial dwarfism, type 1 (2)
2	-	-	RNU4ATAC-related disorder (2)
1	-	-	CLASP1-related disorder (1)
1	-	-	Hydrocephalus, nonsyndromic, autosomal recessive 1 (1)
1	-	-	Lowry-Wood syndrome (1)
1	-	-	RNU4ATAC spectrum disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Benign	0.91
PhyloP100		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=23/77	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs188343279; hg19: chr2-122288506;