3-124326102-C-T

Variant names:

• chr3-124326102-C-T
• rs2289778
• NM_001388419.1:c.1215C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BA1

The NM_001388419.1(KALRN):​c.1215C>T​(p.Phe405Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.879 in 1,613,528 control chromosomes in the GnomAD database, including 628,584 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (50198 hom., cov: 32)
  • Exomes 𝑓: 0.89 (578386 hom.)
• Consequence: KALRN NM_001388419.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.415

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.246).
• BP6: Variant 3-124326102-C-T is Benign according to our data. Variant chr3-124326102-C-T is described in ClinVar as [Benign]. Clinvar id is 1277522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.415 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.896 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KALRN	NM_001388419.1	c.1215C>T	p.Phe405Phe	synonymous_variant	Exon 7 of 60	ENST00000682506.1	NP_001375348.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KALRN	ENST00000682506.1	c.1215C>T	p.Phe405Phe	synonymous_variant	Exon 7 of 60		NM_001388419.1	ENSP00000508359.1

Frequencies

GnomAD3 genomes AF: 0.800 AC: 121598 AN: 152018 Hom.: 50171 Cov.: 32

Gnomad AFR AF: 0.581

Gnomad AMI AF: 0.844

Gnomad AMR AF: 0.828

Gnomad ASJ AF: 0.842

Gnomad EAS AF: 0.775

Gnomad SAS AF: 0.892

Gnomad FIN AF: 0.906

Gnomad MID AF: 0.832

Gnomad NFE AF: 0.902

Gnomad OTH AF: 0.807

GnomAD2 exomes AF: 0.859 AC: 215370 AN: 250772 AF XY: 0.867

Gnomad AFR exome AF: 0.571

Gnomad AMR exome AF: 0.841

Gnomad ASJ exome AF: 0.838

Gnomad EAS exome AF: 0.777

Gnomad FIN exome AF: 0.906

Gnomad NFE exome AF: 0.905

Gnomad OTH exome AF: 0.864

GnomAD4 exome AF: 0.888 AC: 1297320 AN: 1461392 Hom.: 578386 Cov.: 51 AF XY: 0.888 AC XY: 645651 AN XY: 726966

African (AFR) AF: 0.572 AC: 19159 AN: 33466

American (AMR) AF: 0.836 AC: 37369 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.837 AC: 21885 AN: 26134

East Asian (EAS) AF: 0.768 AC: 30463 AN: 39690

South Asian (SAS) AF: 0.884 AC: 76146 AN: 86122

European-Finnish (FIN) AF: 0.904 AC: 48315 AN: 53418

Middle Eastern (MID) AF: 0.870 AC: 5016 AN: 5768

European-Non Finnish (NFE) AF: 0.905 AC: 1006638 AN: 1111734

Other (OTH) AF: 0.867 AC: 52329 AN: 60382

GnomAD4 genome AF: 0.800 AC: 121674 AN: 152136 Hom.: 50198 Cov.: 32 AF XY: 0.802 AC XY: 59679 AN XY: 74378

African (AFR) AF: 0.581 AC: 24074 AN: 41440

American (AMR) AF: 0.828 AC: 12660 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.842 AC: 2922 AN: 3472

East Asian (EAS) AF: 0.776 AC: 3998 AN: 5150

South Asian (SAS) AF: 0.893 AC: 4312 AN: 4828

European-Finnish (FIN) AF: 0.906 AC: 9608 AN: 10610

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.902 AC: 61381 AN: 68026

Other (OTH) AF: 0.807 AC: 1705 AN: 2112

Alfa AF: 0.868 Hom.: 235542

Bravo AF: 0.783

Asia WGS AF: 0.827 AC: 2875 AN: 3478

EpiCase AF: 0.898

EpiControl AF: 0.894

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 27, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

KALRN-related disorder Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.41
DANN	Benign	0.71
PhyloP100		-0.41
Mutation Taster		=93/7	polymorphism (auto)

Splicing

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

Publications

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Other links and lift over

dbSNP: rs2289778; hg19: chr3-124044949; COSMIC: COSV108056534; COSMIC: COSV108056534;