3-124334472-G-A

Position:

• chr3-124334472-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP6_Moderate

The NM_001388419.1(KALRN):​c.1624G>A​(p.Val542Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,292 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KALRN NM_001388419.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 10.0

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KALRN
• BP6: Variant 3-124334472-G-A is Benign according to our data. Variant chr3-124334472-G-A is described in ClinVar as [Benign]. Clinvar id is 1685329.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KALRN	NM_001388419.1	c.1624G>A	p.Val542Ile	missense_variant	9/60	ENST00000682506.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KALRN	ENST00000682506.1	c.1624G>A	p.Val542Ile	missense_variant	9/60		NM_001388419.1	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461292 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726954

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	0.0042	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.010	T;.;T;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.61	D;D;D;D
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.22	N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.050	D;D;D;D
Sift4G	Uncertain	0.056	T;T;D;D
Polyphen		0.95	P;P;.;.
Vest4		0.42
MutPred		0.48		Loss of MoRF binding (P = 0.1261);Loss of MoRF binding (P = 0.1261);Loss of MoRF binding (P = 0.1261);.;
MVP		0.62
MPC		0.52
ClinPred		0.91	D
GERP RS		5.3
gMVP		0.16

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1056310843; hg19: chr3-124053319;