chr3-124395221-G-A

Variant names:

• chr3-124395221-G-A
• rs9841322
• NM_001388419.1:c.2049G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6 BP7 BA1

The NM_001388419.1(KALRN):​c.2049G>A​(p.Lys683Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,612,574 control chromosomes in the GnomAD database, including 19,023 homozygotes. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.12 (1273 hom., cov: 30)
  • Exomes 𝑓: 0.15 (17750 hom.)
• Consequence: KALRN NM_001388419.1 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.534
• Publications: 8 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 -10 ACMG points.

• BP6: Variant 3-124395221-G-A is Benign according to our data. Variant chr3-124395221-G-A is described in ClinVar as Benign. ClinVar VariationId is 3056443.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.534 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.162 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.2049G>A	p.Lys683Lys	synonymous	Exon 12 of 60	NP_001375348.1	O60229-7
	KALRN	NM_001024660.5		c.2043G>A	p.Lys681Lys	synonymous	Exon 12 of 60	NP_001019831.2	O60229-1
	KALRN	NM_001322988.2		c.2043G>A	p.Lys681Lys	synonymous	Exon 12 of 49	NP_001309917.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	ENST00000682506.1	MANE Select	c.2049G>A	p.Lys683Lys	synonymous	Exon 12 of 60	ENSP00000508359.1	O60229-7
	KALRN	ENST00000240874.7	TSL:1	c.2043G>A	p.Lys681Lys	synonymous	Exon 12 of 34	ENSP00000240874.3	O60229-2
	KALRN	ENST00000460856.5	TSL:1	c.2043G>A	p.Lys681Lys	synonymous	Exon 12 of 34	ENSP00000418611.1	C9IZQ6

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17657 AN: 150956 Hom.: 1274 Cov.: 30

Gnomad AFR AF: 0.0393

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.0215

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.152

GnomAD2 exomes AF: 0.127 AC: 31693 AN: 250468 AF XY: 0.130

Gnomad AFR exome AF: 0.0349

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.0226

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.138

GnomAD4 exome AF: 0.151 AC: 220341 AN: 1461500 Hom.: 17750 Cov.: 32 AF XY: 0.150 AC XY: 109186 AN XY: 727052

African (AFR) AF: 0.0341 AC: 1142 AN: 33474

American (AMR) AF: 0.113 AC: 5037 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 3483 AN: 26130

East Asian (EAS) AF: 0.0186 AC: 737 AN: 39692

South Asian (SAS) AF: 0.112 AC: 9626 AN: 86244

European-Finnish (FIN) AF: 0.134 AC: 7149 AN: 53398

Middle Eastern (MID) AF: 0.102 AC: 589 AN: 5766

European-Non Finnish (NFE) AF: 0.166 AC: 183996 AN: 1111692

Other (OTH) AF: 0.142 AC: 8582 AN: 60386

GnomAD4 genome AF: 0.117 AC: 17655 AN: 151074 Hom.: 1273 Cov.: 30 AF XY: 0.115 AC XY: 8488 AN XY: 73716

African (AFR) AF: 0.0392 AC: 1615 AN: 41156

American (AMR) AF: 0.133 AC: 2006 AN: 15054

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 446 AN: 3464

East Asian (EAS) AF: 0.0217 AC: 112 AN: 5154

South Asian (SAS) AF: 0.105 AC: 498 AN: 4742

European-Finnish (FIN) AF: 0.129 AC: 1337 AN: 10378

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.164 AC: 11154 AN: 67840

Other (OTH) AF: 0.150 AC: 314 AN: 2088

Alfa AF: 0.147 Hom.: 1191

Bravo AF: 0.115

Asia WGS AF: 0.0810 AC: 281 AN: 3478

EpiCase AF: 0.162

EpiControl AF: 0.165

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	-0.45
CADD	Benign	6.6
DANN	Benign	0.62
PhyloP100		0.53
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs9841322; hg19: chr3-124114068; COSMIC: COSV53757850;