NM_001388419.1:c.73+21418T>G

Variant names:

• chr3-124055231-T-G
• rs9289231
• NM_001388419.1:c.73+21418T>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001388419.1(KALRN):​c.73+21418T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 152,212 control chromosomes in the GnomAD database, including 2,094 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.14 (2094 hom., cov: 32)
• Consequence: KALRN NM_001388419.1 intron
• Clinical Significance: Benign criteria provided, single submitter P:1 B:2
• Conservation: PhyloP100: 1.02

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 3-124055231-T-G is Benign according to our data. Variant chr3-124055231-T-G is described in ClinVar as [Benign]. Clinvar id is 5458.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KALRN	NM_001388419.1	c.73+21418T>G		intron_variant	Intron 1 of 59	ENST00000682506.1	NP_001375348.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KALRN	ENST00000682506.1	c.73+21418T>G		intron_variant	Intron 1 of 59		NM_001388419.1	ENSP00000508359.1
KALRN	ENST00000683571.1	c.73+21418T>G		intron_variant	Intron 1 of 3			ENSP00000506888.1
KALRN	ENST00000682861.1	c.73+21418T>G		intron_variant	Intron 1 of 1			ENSP00000506756.1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21594 AN: 152094 Hom.: 2087 Cov.: 32

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.0931

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.0115

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0957

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0913

Gnomad OTH AF: 0.114

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

GnomAD4 genome AF: 0.142 AC: 21633 AN: 152212 Hom.: 2094 Cov.: 32 AF XY: 0.141 AC XY: 10508 AN XY: 74422

Gnomad4 AFR AF: 0.279

Gnomad4 AMR AF: 0.0929

Gnomad4 ASJ AF: 0.123

Gnomad4 EAS AF: 0.0112

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.0957

Gnomad4 NFE AF: 0.0913

Gnomad4 OTH AF: 0.114

Alfa AF: 0.105 Hom.: 1437

Bravo AF: 0.147

Asia WGS AF: 0.0770 AC: 268 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Coronary heart disease, susceptibility to, 5 Pathogenic:1 Benign:1

Apr 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 07, 2025

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. GnomAD 4.1.0 frequency 0.1421 2094 homozygotes -

KALRN-related disorder Benign:1

Feb 22, 2021

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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
BayesDel_noAF	Benign	-0.73
CADD	Benign	14
DANN	Benign	0.67

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs9289231; hg19: chr3-123774078;