chr3-124434444-C-G

Variant names:

• chr3-124434444-C-G
• rs144113221
• NM_001388419.1:c.2967C>G

Variant summary

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

The NM_001388419.1(KALRN):​c.2967C>G​(p.His989Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H989H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KALRN NM_001388419.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.25
• Publications: 0 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KALRN	NM_001388419.1	c.2967C>G	p.His989Gln	missense_variant	Exon 17 of 60	ENST00000682506.1	NP_001375348.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KALRN	ENST00000682506.1	c.2967C>G	p.His989Gln	missense_variant	Exon 17 of 60		NM_001388419.1	ENSP00000508359.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.050	T;.;T
Eigen	Benign	0.098
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.7	.;L;.
PhyloP100		2.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.4	D;D;D
REVEL	Benign	0.19
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.61
MutPred		0.51		.;Gain of MoRF binding (P = 0.086);Gain of MoRF binding (P = 0.086);
MVP		0.44
MPC		1.5
ClinPred		0.99	D
GERP RS		4.2
gMVP		0.61
Mutation Taster		=48/52	disease causing

Splicing

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

Other links and lift over

dbSNP: rs144113221; hg19: chr3-124153291;