3-124347234-AGAGGCATGATGACTTTGAAGAGGTGGCTCAGGTGAGAAGCTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTCTAGATGAGG-A

Variant names:

• chr3-124347234-AGAGGCATGATGACTTTGAAGAGGTGGCTCAGGTGAGAAGCTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTCTAGATGAGG-A
• NM_001388419.1:c.1770+43_1770+139delGTGTGTGTGTGTGTCTAGATGAGGGAGGCATGATGACTTTGAAGAGGTGGCTCAGGTGAGAAGCTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PVS1 BP6

The ENST00000682506.1(KALRN):​c.1740_1770+66delGAGGCATGATGACTTTGAAGAGGTGGCTCAGGTGAGAAGCTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTCTAGATGAGG​(p.Arg581ThrfsTer69) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KALRN ENST00000682506.1 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 10.0

Genes affected

KALRN (HGNC:4814): (kalirin RhoGEF kinase) Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein that interacts with the huntingtin-associated protein 1, which is a huntingtin binding protein that may function in vesicle trafficking. [provided by RefSeq, Apr 2016]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 3-124347234-AGAGGCATGATGACTTTGAAGAGGTGGCTCAGGTGAGAAGCTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTCTAGATGAGG-A is Benign according to our data. Variant chr3-124347234-AGAGGCATGATGACTTTGAAGAGGTGGCTCAGGTGAGAAGCTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTCTAGATGAGG-A is described in ClinVar as [Likely_benign]. Clinvar id is 3033496.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KALRN	NM_001388419.1	c.1770+43_1770+139delGTGTGTGTGTGTGTCTAGATGAGGGAGGCATGATGACTTTGAAGAGGTGGCTCAGGTGAGAAGCTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT		intron_variant	Intron 10 of 59	ENST00000682506.1	NP_001375348.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KALRN	ENST00000682506.1	c.1740_1770+66delGAGGCATGATGACTTTGAAGAGGTGGCTCAGGTGAGAAGCTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTCTAGATGAGG	p.Arg581ThrfsTer69	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 10 of 60		NM_001388419.1	ENSP00000508359.1

Frequencies

GnomAD3 genomes AF: 0.0000338 AC: 5 AN: 147912 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000201

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000298

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000144 AC: 21 AN: 1460174 Hom.: 0 AF XY: 0.0000165 AC XY: 12 AN XY: 726408

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.0000448 AC: 2 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.0000761 AC: 3 AN: 39420

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86202

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111076

Other (OTH) AF: 0.0000332 AC: 2 AN: 60256

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000338 AC: 5 AN: 148028 Hom.: 0 Cov.: 32 AF XY: 0.0000554 AC XY: 4 AN XY: 72148

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

African (AFR) AF: 0.00 AC: 0 AN: 39566

American (AMR) AF: 0.000201 AC: 3 AN: 14958

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3414

East Asian (EAS) AF: 0.00 AC: 0 AN: 5010

South Asian (SAS) AF: 0.00 AC: 0 AN: 4652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.0000298 AC: 2 AN: 67094

Other (OTH) AF: 0.00 AC: 0 AN: 2054

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.086178), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

KALRN-related disorder Benign:1

Dec 29, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=3/197	disease causing (fs/PTC)

Splicing

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

Publications

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Other links and lift over

hg19: chr3-124066081;