chr13-70107612-C-G

Variant names:

• chr13-70107612-C-G
• rs147322205
• NM_020866.3:c.88G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020866.3(KLHL1):​c.88G>C​(p.Gly30Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,437,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G30S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: KLHL1 NM_020866.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.372
• Publications: 4 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18973103).

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.88G>C	p.Gly30Arg	missense	Exon 1 of 11	NP_065917.1	Q9NR64
	KLHL1	NM_001286725.2		c.88G>C	p.Gly30Arg	missense	Exon 1 of 10	NP_001273654.1	F5H1J3
	ATXN8OS	NR_002717.3		n.192C>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.88G>C	p.Gly30Arg	missense	Exon 1 of 11	ENSP00000367075.4	Q9NR64
	KLHL1	ENST00000545028.2	TSL:2	c.88G>C	p.Gly30Arg	missense	Exon 1 of 10	ENSP00000439602.2	F5H1J3
	ATXN8OS	ENST00000414504.6	TSL:5	n.400C>G		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000450 AC: 1 AN: 222026 AF XY: 0.00000834

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000190

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437038 Hom.: 0 Cov.: 33 AF XY: 0.00000140 AC XY: 1 AN XY: 713168

African (AFR) AF: 0.00 AC: 0 AN: 32722

American (AMR) AF: 0.00 AC: 0 AN: 41518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23700

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 81796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5568

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100706

Other (OTH) AF: 0.0000169 AC: 1 AN: 59238

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.37
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.26
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.023	D
Polyphen		0.99	D
Vest4		0.33
MutPred		0.24		Gain of catalytic residue at A33 (P = 0)
MVP		0.79
MPC		0.070
ClinPred		0.23	T
GERP RS		1.7
Varity_R		0.055
gMVP		0.30
Mutation Taster		=99/1	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: rs147322205; hg19: chr13-70681744;