Genetic Variant LRIG2:c.306-2A>G (chr1-113093204-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_014813.3(LRIG2):c.306-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,427,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

LRIG2
NM_014813.3 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 8.79

Publications

0 publications found

Variant links:

Genes affected

LRIG2 (HGNC:20889): (leucine rich repeats and immunoglobulin like domains 2) This gene encodes a transmembrane protein containing leucine-rich repeats and immunoglobulin-like domains. The encoded protein promotes epidermal growth factor signalling, resulting in increased proliferation. Its expression in the cytoplasm of glioma cells is correlated with poor survival. Mutations in this gene can cause urofacial syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

LRIG2 Gene-Disease associations (from GenCC):

urofacial syndrome 2
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
Ochoa syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LRIG2 links:

ENSG00000303525 (HGNC:):

ENSG00000303525 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.023452157 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-113093204-A-G is Pathogenic according to our data. Variant chr1-113093204-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1065942.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014813.3. 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
	LRIG2	NM_014813.3	MANE Select	c.306-2A>G		splice_acceptor intron	N/A	NP_055628.1	O94898
	LRIG2	NM_001312686.2		c.-4-2A>G		splice_acceptor intron	N/A	NP_001299615.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LRIG2	ENST00000361127.6	TSL:1 MANE Select	c.306-2A>G	splice_acceptor intron	N/A	ENSP00000355396.4	O94898
LRIG2	ENST00000922864.1		c.306-2A>G	splice_acceptor intron	N/A	ENSP00000592923.1
LRIG2	ENST00000890456.1		c.240-2A>G	splice_acceptor intron	N/A	ENSP00000560515.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

234586

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000112

AC:

AN:

1427890

Hom.:

Cov.:

AF XY:

0.0000155

AC XY:

AN XY:

710750

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32626

American (AMR)

AF:

0.00

AC:

AN:

41986

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25698

East Asian (EAS)

AF:

0.00

AC:

AN:

39396

South Asian (SAS)

AF:

0.00

AC:

AN:

81680

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53044

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.0000138

AC:

AN:

1088530

Other (OTH)

AF:

0.0000169

AC:

AN:

59230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

PhyloP100

8.8

GERP RS

5.5

Mutation Taster

=1/99

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.97

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.97

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over