chr10-132785828-T-A

Variant names:

• chr10-132785828-T-A
• rs1131692047
• NM_177400.3:c.121A>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 18P and 1B. PVS1 PM2 PP5_Very_Strong BS1_Supporting

The NM_177400.3(NKX6-2):​c.121A>T​(p.Lys41*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000568 in 1,231,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: NKX6-2 NM_177400.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 1.53
• Publications: 3 publications found

Genes affected

NKX6-2 (HGNC:19321): (NK6 homeobox 2) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in cell differentiation; regulation of myelination; and regulation of transcription, DNA-templated. Predicted to act upstream of or within several processes, including negative regulation of transcription by RNA polymerase II; neurogenesis; and neuromuscular process controlling balance. Predicted to be part of chromatin. Predicted to be active in nucleus. Implicated in spastic ataxia 8. [provided by Alliance of Genome Resources, Apr 2022]

NKX6-2 Gene-Disease associations (from GenCC):

• spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-132785828-T-A is Pathogenic according to our data. Variant chr10-132785828-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 430622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00000568 (7/1231912) while in subpopulation SAS AF = 0.000125 (7/56214). AF 95% confidence interval is 0.0000576. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 23. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX6-2	NM_177400.3	c.121A>T	p.Lys41*	stop_gained	Exon 1 of 3	ENST00000368592.8	NP_796374.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX6-2	ENST00000368592.8	c.121A>T	p.Lys41*	stop_gained	Exon 1 of 3	1	NM_177400.3	ENSP00000357581.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000568 AC: 7 AN: 1231912 Hom.: 0 Cov.: 23 AF XY: 0.00000329 AC XY: 2 AN XY: 608672

African (AFR) AF: 0.00 AC: 0 AN: 25204

American (AMR) AF: 0.00 AC: 0 AN: 21552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17722

East Asian (EAS) AF: 0.00 AC: 0 AN: 29640

South Asian (SAS) AF: 0.000125 AC: 7 AN: 56214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 996692

Other (OTH) AF: 0.00 AC: 0 AN: 48898

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy Pathogenic:5 Other:1

Dec 18, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 18, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 17, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Feb 27, 2020

Yale Center for Mendelian Genomics, Yale University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.82	D
PhyloP100		1.5
Vest4		0.73
GERP RS		3.1
PromoterAI		-0.0025	Neutral
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1131692047; hg19: chr10-134599332;