NM_001388419.1:c.132G>A

Variant names:

• chr3-124228048-G-A
• rs2293641
• NM_001388419.1:c.132G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4 BP6 BP7 BA1

The NM_001388419.1(KALRN):​c.132G>A​(p.Lys44Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0604 in 1,613,456 control chromosomes in the GnomAD database, including 4,897 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.099 (1132 hom., cov: 31)
  • Exomes 𝑓: 0.056 (3765 hom.)
• Consequence: KALRN NM_001388419.1 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.01
• Publications: 10 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.207).
• BP6: Variant 3-124228048-G-A is Benign according to our data. Variant chr3-124228048-G-A is described in ClinVar as Benign. ClinVar VariationId is 3060740.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=3.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	NM_001388419.1	MANE Select	c.132G>A	p.Lys44Lys	synonymous	Exon 2 of 60	NP_001375348.1	O60229-7
	KALRN	NM_001024660.5		c.126G>A	p.Lys42Lys	synonymous	Exon 2 of 60	NP_001019831.2	O60229-1
	KALRN	NM_001322988.2		c.126G>A	p.Lys42Lys	synonymous	Exon 2 of 49	NP_001309917.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	ENST00000682506.1	MANE Select	c.132G>A	p.Lys44Lys	synonymous	Exon 2 of 60	ENSP00000508359.1	O60229-7
	KALRN	ENST00000240874.7	TSL:1	c.126G>A	p.Lys42Lys	synonymous	Exon 2 of 34	ENSP00000240874.3	O60229-2
	KALRN	ENST00000460856.5	TSL:1	c.126G>A	p.Lys42Lys	synonymous	Exon 2 of 34	ENSP00000418611.1	C9IZQ6

Frequencies

GnomAD3 genomes AF: 0.0989 AC: 15037 AN: 152036 Hom.: 1129 Cov.: 31

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0513

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.0564

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0382

Gnomad OTH AF: 0.0800

GnomAD2 exomes AF: 0.0896 AC: 22534 AN: 251414 AF XY: 0.0831

Gnomad AFR exome AF: 0.204

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.0590

Gnomad EAS exome AF: 0.183

Gnomad FIN exome AF: 0.0526

Gnomad NFE exome AF: 0.0389

Gnomad OTH exome AF: 0.0779

GnomAD4 exome AF: 0.0563 AC: 82344 AN: 1461302 Hom.: 3765 Cov.: 30 AF XY: 0.0564 AC XY: 41010 AN XY: 726974

African (AFR) AF: 0.216 AC: 7234 AN: 33456

American (AMR) AF: 0.162 AC: 7265 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0594 AC: 1552 AN: 26128

East Asian (EAS) AF: 0.186 AC: 7376 AN: 39688

South Asian (SAS) AF: 0.104 AC: 8934 AN: 86234

European-Finnish (FIN) AF: 0.0541 AC: 2890 AN: 53418

Middle Eastern (MID) AF: 0.0758 AC: 437 AN: 5764

European-Non Finnish (NFE) AF: 0.0380 AC: 42282 AN: 1111520

Other (OTH) AF: 0.0724 AC: 4374 AN: 60374

GnomAD4 genome AF: 0.0990 AC: 15069 AN: 152154 Hom.: 1132 Cov.: 31 AF XY: 0.101 AC XY: 7514 AN XY: 74398

African (AFR) AF: 0.198 AC: 8205 AN: 41486

American (AMR) AF: 0.119 AC: 1824 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0513 AC: 178 AN: 3472

East Asian (EAS) AF: 0.180 AC: 934 AN: 5178

South Asian (SAS) AF: 0.109 AC: 528 AN: 4822

European-Finnish (FIN) AF: 0.0564 AC: 597 AN: 10590

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0382 AC: 2598 AN: 68010

Other (OTH) AF: 0.0801 AC: 169 AN: 2110

Alfa AF: 0.0684 Hom.: 448

Bravo AF: 0.109

Asia WGS AF: 0.176 AC: 610 AN: 3478

EpiCase AF: 0.0421

EpiControl AF: 0.0412

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	KALRN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.62
PhyloP100		3.0
PromoterAI		0.0020	Neutral
Mutation Taster		=95/5	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2293641; hg19: chr3-123946895; COSMIC: COSV53753306;