chr3-124398839-C-A

Variant names:

• chr3-124398839-C-A
• rs150500689
• NM_001388419.1:c.2314C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001388419.1(KALRN):​c.2314C>A​(p.Gln772Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,360 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KALRN NM_001388419.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2314C>A	p.Gln772Lys	missense	Exon 13 of 60	NP_001375348.1
	KALRN	NM_001024660.5		c.2308C>A	p.Gln770Lys	missense	Exon 13 of 60	NP_001019831.2
	KALRN	NM_001322988.2		c.2308C>A	p.Gln770Lys	missense	Exon 13 of 49	NP_001309917.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	ENST00000682506.1	MANE Select	c.2314C>A	p.Gln772Lys	missense	Exon 13 of 60	ENSP00000508359.1
	KALRN	ENST00000240874.7	TSL:1	c.2308C>A	p.Gln770Lys	missense	Exon 13 of 34	ENSP00000240874.3
	KALRN	ENST00000460856.5	TSL:1	c.2308C>A	p.Gln770Lys	missense	Exon 13 of 34	ENSP00000418611.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461360 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726974

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111738

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.21
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.035	D
Polyphen		0.99	D
Vest4		0.77
MutPred		0.70		Gain of ubiquitination at Q770 (P = 0.0219)
MVP		0.61
MPC		1.8
ClinPred		0.97	D
GERP RS		5.3
gMVP		0.75
Mutation Taster		=51/49	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs150500689; hg19: chr3-124117686; COSMIC: COSV104384072; COSMIC: COSV104384072;