rs1131692048

Variant names:

• chr10-132785372-G-C
• rs1131692048
• NM_177400.3:c.487C>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_177400.3(NKX6-2):​c.487C>G​(p.Leu163Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NKX6-2 NM_177400.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 1.47
• Publications: 4 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 16 ACMG points.

• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity NKX62_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_177400.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 10-132785372-G-C is Pathogenic according to our data. Variant chr10-132785372-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 430623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX6-2	NM_177400.3	c.487C>G	p.Leu163Val	missense_variant	Exon 2 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.487C>G	p.Leu163Val	missense_variant	Exon 2 of 3	1	NM_177400.3	ENSP00000357581.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

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

Mar 14, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 27, 2020

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

CENTOGENE GmbH and LLC - Guiding Precision Medicine

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

- -

Jul 07, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 30, 2022

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.71	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.9	H
PhyloP100		1.5
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.92		Gain of methylation at K165 (P = 0.0908);
MVP		0.92
ClinPred		1.0	D
GERP RS		1.8
Varity_R		0.98
gMVP		0.72
Mutation Taster		=16/84	disease causing (ClinVar)

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: rs1131692048; hg19: chr10-134598876;