Genetic Variant NM_001388419.1:c.4936-86G>T (chr3-124562757-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001388419.1(KALRN):c.4936-86G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000975 in 1,025,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 9.8e-7 ( 0 hom. )

Consequence

KALRN
NM_001388419.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.551

Publications

10 publications found

Variant links:

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]

KALRN links:

LOC105374076 (HGNC:):

LOC105374076 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KALRN	NM_001388419.1 link	c.4936-86G>T		intron_variant	Intron 33 of 59	ENST00000682506.1	NP_001375348.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KALRN	ENST00000682506.1 link	c.4936-86G>T		intron_variant	Intron 33 of 59		NM_001388419.1	ENSP00000508359.1		A0A804HLI0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.75e-7

AC:

AN:

1025580

Hom.:

Cov.:

AF XY:

0.00000202

AC XY:

AN XY:

495782

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

21952

American (AMR)

AF:

0.00

AC:

AN:

22544

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11280

East Asian (EAS)

AF:

0.00

AC:

AN:

11820

South Asian (SAS)

AF:

0.0000156

AC:

AN:

63940

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3960

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

833896

Other (OTH)

AF:

0.00

AC:

AN:

36882

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

1959

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.19

(source)

DANN

Benign

0.45

PhyloP100

-0.55

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over