NM_020866.3:c.183G>C

Variant names:

• chr13-70107517-C-G
• rs111324959
• NM_020866.3:c.183G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020866.3(KLHL1):​c.183G>C​(p.Glu61Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000438 in 1,612,850 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: KLHL1 NM_020866.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 1.06
• Publications: 0 publications found

Genes affected

KLHL1 (HGNC:6352): (kelch like family member 1) The KLHL1 protein belongs to a family of actin-organizing proteins related to Drosophila Kelch (Nemes et al., 2000 [PubMed 10888605]).[supplied by OMIM, Feb 2010]

ATXN8OS (HGNC:10561): (ATXN8 opposite strand lncRNA) This gene is an antisense transcript to the KLHL1 gene (homolog to the Drosophila KELCH gene); it does not itself appear to be protein coding. A TAC/TGC trinucleotide repeat expansion that is incorporated into this gene transcript, but not the KLHL1 transcript, causes spinocerebellar ataxia type 8. Presumably the expansion interferes with normal antisense function of this transcript. [provided by RefSeq, Oct 2008]

ATXN8OS Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 8

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058128834).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020866.3. 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
	KLHL1	NM_020866.3	MANE Select	c.183G>C	p.Glu61Asp	missense	Exon 1 of 11	NP_065917.1	Q9NR64
	KLHL1	NM_001286725.2		c.183G>C	p.Glu61Asp	missense	Exon 1 of 10	NP_001273654.1	F5H1J3
	ATXN8OS	NR_002717.3		n.97C>G		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL1	ENST00000377844.9	TSL:1 MANE Select	c.183G>C	p.Glu61Asp	missense	Exon 1 of 11	ENSP00000367075.4	Q9NR64
	KLHL1	ENST00000545028.2	TSL:2	c.183G>C	p.Glu61Asp	missense	Exon 1 of 10	ENSP00000439602.2	F5H1J3
	ATXN8OS	ENST00000414504.6	TSL:5	n.305C>G		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.00224 AC: 341 AN: 152184 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000586 AC: 145 AN: 247474 AF XY: 0.000388

Gnomad AFR exome AF: 0.00757

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000248 AC: 362 AN: 1460548 Hom.: 1 Cov.: 33 AF XY: 0.000220 AC XY: 160 AN XY: 726506

African (AFR) AF: 0.00833 AC: 279 AN: 33474

American (AMR) AF: 0.000627 AC: 28 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25956

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5758

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111196

Other (OTH) AF: 0.000763 AC: 46 AN: 60326

GnomAD4 genome AF: 0.00227 AC: 345 AN: 152302 Hom.: 1 Cov.: 33 AF XY: 0.00216 AC XY: 161 AN XY: 74466

African (AFR) AF: 0.00779 AC: 324 AN: 41582

American (AMR) AF: 0.00124 AC: 19 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000256 Hom.: 0

Bravo AF: 0.00250

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000749 AC: 91

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	KLHL1-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	14
DANN	Benign	0.70
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.074
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.1
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.18
Sift	Benign	0.68	T
Sift4G	Benign	0.79	T
Polyphen		0.96	P
Vest4		0.29
MutPred		0.23		Loss of helix (P = 0.079)
MVP		0.78
MPC		0.16
ClinPred		0.040	T
GERP RS		3.3
Varity_R		0.049
gMVP		0.26
Mutation Taster		=298/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs111324959; hg19: chr13-70681649;