chr6-18122295-A-G

Variant names:

• chr6-18122295-A-G
• rs115931931
• NM_198586.3:c.312T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198586.3(NHLRC1):​c.312T>C​(p.His104His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0956 in 1,593,860 control chromosomes in the GnomAD database, including 8,055 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1232 hom., cov: 33)
  • Exomes 𝑓: 0.094 (6823 hom.)
• Consequence: NHLRC1 NM_198586.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.631
• Publications: 9 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-18122295-A-G is Benign according to our data. Variant chr6-18122295-A-G is described in ClinVar as Benign. ClinVar VariationId is 129766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHLRC1	NM_198586.3	c.312T>C	p.His104His	synonymous_variant	Exon 1 of 1	ENST00000340650.6	NP_940988.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHLRC1	ENST00000340650.6	c.312T>C	p.His104His	synonymous_variant	Exon 1 of 1	6	NM_198586.3	ENSP00000345464.3

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17446 AN: 152110 Hom.: 1230 Cov.: 33

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.0628

Gnomad AMR AF: 0.0983

Gnomad ASJ AF: 0.0775

Gnomad EAS AF: 0.0142

Gnomad SAS AF: 0.0816

Gnomad FIN AF: 0.0607

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0906

Gnomad OTH AF: 0.117

GnomAD2 exomes AF: 0.0861 AC: 18216 AN: 211654 AF XY: 0.0843

Gnomad AFR exome AF: 0.199

Gnomad AMR exome AF: 0.0820

Gnomad ASJ exome AF: 0.0738

Gnomad EAS exome AF: 0.0143

Gnomad FIN exome AF: 0.0721

Gnomad NFE exome AF: 0.0895

Gnomad OTH exome AF: 0.0906

GnomAD4 exome AF: 0.0936 AC: 134892 AN: 1441632 Hom.: 6823 Cov.: 36 AF XY: 0.0923 AC XY: 66167 AN XY: 716930

African (AFR) AF: 0.202 AC: 6747 AN: 33346

American (AMR) AF: 0.0840 AC: 3632 AN: 43242

Ashkenazi Jewish (ASJ) AF: 0.0773 AC: 2000 AN: 25864

East Asian (EAS) AF: 0.0131 AC: 518 AN: 39518

South Asian (SAS) AF: 0.0791 AC: 6783 AN: 85712

European-Finnish (FIN) AF: 0.0742 AC: 2953 AN: 39818

Middle Eastern (MID) AF: 0.0814 AC: 465 AN: 5710

European-Non Finnish (NFE) AF: 0.0959 AC: 106321 AN: 1108460

Other (OTH) AF: 0.0913 AC: 5473 AN: 59962

GnomAD4 genome AF: 0.115 AC: 17460 AN: 152228 Hom.: 1232 Cov.: 33 AF XY: 0.111 AC XY: 8300 AN XY: 74444

African (AFR) AF: 0.195 AC: 8095 AN: 41570

American (AMR) AF: 0.0981 AC: 1501 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0775 AC: 269 AN: 3472

East Asian (EAS) AF: 0.0142 AC: 73 AN: 5146

South Asian (SAS) AF: 0.0810 AC: 391 AN: 4826

European-Finnish (FIN) AF: 0.0607 AC: 644 AN: 10616

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0906 AC: 6157 AN: 67984

Other (OTH) AF: 0.115 AC: 243 AN: 2114

Alfa AF: 0.0886 Hom.: 830

Bravo AF: 0.121

Asia WGS AF: 0.0660 AC: 230 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Lafora disease Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Mar 18, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.6
DANN	Benign	0.45
PhyloP100		-0.63
PromoterAI		-0.035	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs115931931; hg19: chr6-18122526; COSMIC: COSV61481531;