chr3-124659390-G-A

Variant names:

• chr3-124659390-G-A
• rs141343989
• NM_001388419.1:c.6149G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001388419.1(KALRN):​c.6149G>A​(p.Arg2050Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,366 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: 0.0000062 (0 hom.)
• Consequence: KALRN NM_001388419.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.12
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21763232).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001388419.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	NM_001388419.1	MANE Select	c.6149G>A	p.Arg2050Lys	missense	Exon 43 of 60	NP_001375348.1
	KALRN	NM_001024660.5		c.6146G>A	p.Arg2049Lys	missense	Exon 43 of 60	NP_001019831.2
	KALRN	NM_001322988.2		c.6143G>A	p.Arg2048Lys	missense	Exon 43 of 49	NP_001309917.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	ENST00000682506.1	MANE Select	c.6149G>A	p.Arg2050Lys	missense	Exon 43 of 60	ENSP00000508359.1
	KALRN	ENST00000291478.9	TSL:1	c.1055G>A	p.Arg352Lys	missense	Exon 10 of 27	ENSP00000291478.4
	KALRN	ENST00000360013.7	TSL:5	c.6146G>A	p.Arg2049Lys	missense	Exon 43 of 60	ENSP00000353109.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461366 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727026

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111546

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.74	T
PhyloP100		8.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.24
Sift	Benign	0.43	T
Sift4G	Benign	0.38	T
Vest4		0.35
MVP		0.76
ClinPred		0.89	D
GERP RS		4.7
Mutation Taster		=60/40	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs141343989; hg19: chr3-124378237;