2-98217873-AAA-CGC

Variant names:

• chr2-98217873-AAA-CGC
• NM_144992.5:c.1864_1866delAAAinsCGC
• VWA3B p.Lys622Arg

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM5

The NM_144992.5(VWA3B):​c.1864_1866delAAAinsCGC​(p.Lys622Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K622T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VWA3B NM_144992.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.63
• Publications: 0 publications found

Genes affected

VWA3B (HGNC:28385): (von Willebrand factor A domain containing 3B) This gene encodes an intracellular protein that contains a von Willebrand factor type A domain. Intracellular proteins with VWA domains are thought to function in transcription, DNA repair, ribosomal and membrane transport and the proteasome. Mutations in this gene are associated with Spinocerebellar ataxia, autosomal recessive 22. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, May 2017]

VWA3B Gene-Disease associations (from GenCC):

• spinocerebellar ataxia, autosomal recessive 22

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-98217874-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 226428.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144992.5. 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
	VWA3B	NM_144992.5	MANE Select	c.1864_1866delAAAinsCGC	p.Lys622Arg	missense	N/A	NP_659429.4
	VWA3B	NM_001345864.2		c.835_837delAAAinsCGC	p.Lys279Arg	missense	N/A	NP_001332793.1
	VWA3B	NR_144296.2		n.2152_2154delAAAinsCGC		non_coding_transcript_exon	Exon 14 of 29

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWA3B	ENST00000477737.6	TSL:1 MANE Select	c.1864_1866delAAAinsCGC	p.Lys622Arg	missense	N/A	ENSP00000417955.1	Q502W6-1
	VWA3B	ENST00000409460.5	TSL:1	n.2070_2072delAAAinsCGC		non_coding_transcript_exon	Exon 14 of 23
	VWA3B	ENST00000416277.5	TSL:1	n.*511_*513delAAAinsCGC		non_coding_transcript_exon	Exon 14 of 19	ENSP00000411168.1	F8WBX4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-98834336;