chr3-124269192-T-A

Variant names:

• chr3-124269192-T-A
• rs2272486
• NM_001388419.1:c.906T>A

Variant summary

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

The NM_001024660.5(KALRN):​c.900T>A​(p.His300Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. H300H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KALRN NM_001024660.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.68
• Publications: 14 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_001024660.5. 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.906T>A	p.His302Gln	missense	Exon 5 of 60	NP_001375348.1
	KALRN	NM_001024660.5		c.900T>A	p.His300Gln	missense	Exon 5 of 60	NP_001019831.2
	KALRN	NM_001322988.2		c.900T>A	p.His300Gln	missense	Exon 5 of 49	NP_001309917.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	ENST00000682506.1	MANE Select	c.906T>A	p.His302Gln	missense	Exon 5 of 60	ENSP00000508359.1
	KALRN	ENST00000240874.7	TSL:1	c.900T>A	p.His300Gln	missense	Exon 5 of 34	ENSP00000240874.3
	KALRN	ENST00000460856.5	TSL:1	c.900T>A	p.His300Gln	missense	Exon 5 of 34	ENSP00000418611.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 56

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.0014	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	3.9
DANN	Benign	0.80
DEOGEN2	Benign	0.079	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.3	L
PhyloP100		-1.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.31
Sift	Benign	0.52	T
Sift4G	Benign	0.63	T
Polyphen		0.23	B
Vest4		0.64
MutPred		0.28		Gain of MoRF binding (P = 0.088)
MVP		0.77
MPC		0.86
ClinPred		0.54	D
GERP RS		-5.8
gMVP		0.80
Mutation Taster		=57/43	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs2272486; hg19: chr3-123988039;