rs1060503098

Variant names:

• chr6-18121916-C-G
• rs1060503098
• NM_198586.3:c.691G>C

Your query was ambiguous. Multiple possible variants found:

• chr6-18121916-C-G
• chr6-18121916-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_198586.3(NHLRC1):​c.691G>C​(p.Val231Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. V231I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NHLRC1 NM_198586.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.95
• Publications: 0 publications found

Genes affected

NHLRC1 (HGNC:21576): (NHL repeat containing E3 ubiquitin protein ligase 1) The protein encoded by this gene is a single subunit E3 ubiquitin ligase. Laforin is polyubiquitinated by the encoded protein. Defects in this intronless gene lead to an accumulation of laforin and onset of Lafora disease, also known as progressive myoclonic epilepsy type 2 (EPM2).[provided by RefSeq, Mar 2010]

NHLRC1 Gene-Disease associations (from GenCC):

• Lafora disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.49521 (below the threshold of 3.09). Trascript score misZ: -0.085446 (below the threshold of 3.09). GenCC associations: The gene is linked to Lafora disease.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198586.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHLRC1	NM_198586.3	MANE Select	c.691G>C	p.Val231Leu	missense	Exon 1 of 1	NP_940988.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHLRC1	ENST00000340650.6	TSL:6 MANE Select	c.691G>C	p.Val231Leu	missense	Exon 1 of 1	ENSP00000345464.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		2.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.047	D
Polyphen		0.14	B
Vest4		0.48
MutPred		0.69		Loss of sheet (P = 0.1158)
MVP		0.86
MPC		0.43
ClinPred		0.91	D
GERP RS		4.1
Varity_R		0.35
gMVP		0.87
Mutation Taster		=86/14	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: rs1060503098; hg19: chr6-18122147;