NM_001388419.1:c.1770+43_1770+139delGTGTGTGTGTGTGTCTAGATGAGGGAGGCATGATGACTTTGAAGAGGTGGCTCAGGTGAGAAGCTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BP6

The NM_001388419.1(KALRN):​c.1770+43_1770+139delGTGTGTGTGTGTGTCTAGATGAGGGAGGCATGATGACTTTGAAGAGGTGGCTCAGGTGAGAAGCTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT variant causes a 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).

• Frequency:
  • Genomes: 𝑓 0.000034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KALRN NM_001388419.1 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

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: Uncertain_significance. The variant received 0 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• 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

Other links and lift over

hg19: chr3-124066081;