NM_001388419.1:c.3120G>A

Variant names:

• chr3-124438959-G-A
• rs2289837
• NM_001388419.1:c.3120G>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.3120G>A​(p.Lys1040Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,614,080 control chromosomes in the GnomAD database, including 305 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (29 hom., cov: 31)
  • Exomes 𝑓: 0.014 (276 hom.)
• Consequence: KALRN NM_001388419.1 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.661
• Publications: 7 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=0.184).
• BP6: Variant 3-124438959-G-A is Benign according to our data. Variant chr3-124438959-G-A is described in ClinVar as Benign. ClinVar VariationId is 3056205.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.661 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0696 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.3120G>A	p.Lys1040Lys	synonymous	Exon 18 of 60	NP_001375348.1	O60229-7
	KALRN	NM_001024660.5		c.3114G>A	p.Lys1038Lys	synonymous	Exon 18 of 60	NP_001019831.2	O60229-1
	KALRN	NM_001322988.2		c.3114G>A	p.Lys1038Lys	synonymous	Exon 18 of 49	NP_001309917.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	ENST00000682506.1	MANE Select	c.3120G>A	p.Lys1040Lys	synonymous	Exon 18 of 60	ENSP00000508359.1	O60229-7
	KALRN	ENST00000240874.7	TSL:1	c.3114G>A	p.Lys1038Lys	synonymous	Exon 18 of 34	ENSP00000240874.3	O60229-2
	KALRN	ENST00000460856.5	TSL:1	c.3087G>A	p.Lys1029Lys	synonymous	Exon 18 of 34	ENSP00000418611.1	C9IZQ6

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1829 AN: 152146 Hom.: 29 Cov.: 31

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.0759

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.0152 AC: 3829 AN: 251216 AF XY: 0.0145

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00992

Gnomad ASJ exome AF: 0.0155

Gnomad EAS exome AF: 0.0778

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.0148

GnomAD4 exome AF: 0.0142 AC: 20685 AN: 1461816 Hom.: 276 Cov.: 31 AF XY: 0.0140 AC XY: 10164 AN XY: 727208

African (AFR) AF: 0.00221 AC: 74 AN: 33478

American (AMR) AF: 0.0113 AC: 504 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0142 AC: 370 AN: 26134

East Asian (EAS) AF: 0.0828 AC: 3285 AN: 39680

South Asian (SAS) AF: 0.00619 AC: 534 AN: 86248

European-Finnish (FIN) AF: 0.0127 AC: 681 AN: 53416

Middle Eastern (MID) AF: 0.00798 AC: 46 AN: 5768

European-Non Finnish (NFE) AF: 0.0128 AC: 14222 AN: 1111978

Other (OTH) AF: 0.0160 AC: 969 AN: 60394

GnomAD4 genome AF: 0.0120 AC: 1831 AN: 152264 Hom.: 29 Cov.: 31 AF XY: 0.0125 AC XY: 929 AN XY: 74434

African (AFR) AF: 0.00258 AC: 107 AN: 41544

American (AMR) AF: 0.0140 AC: 214 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3470

East Asian (EAS) AF: 0.0757 AC: 392 AN: 5176

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4820

European-Finnish (FIN) AF: 0.0121 AC: 129 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0127 AC: 864 AN: 68028

Other (OTH) AF: 0.0161 AC: 34 AN: 2112

Alfa AF: 0.0119 Hom.: 34

Bravo AF: 0.0126

Asia WGS AF: 0.0320 AC: 110 AN: 3478

EpiCase AF: 0.0127

EpiControl AF: 0.0114

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	-0.46
CADD	Benign	4.3
DANN	Benign	0.61
PhyloP100		0.66
Mutation Taster		=98/2	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2289837; hg19: chr3-124157806;