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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, ClinGen

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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHLRC1	NM_198586.3	MANE Select	c.312T>C	p.His104His	synonymous	Exon 1 of 1	NP_940988.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHLRC1	ENST00000340650.6	TSL:6 MANE Select	c.312T>C	p.His104His	synonymous	Exon 1 of 1	ENSP00000345464.3	Q6VVB1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Lafora disease (3)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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;