chr1-153261012-C-CGGCGGTGGCGGT

Variant names:

• chr1-153261012-C-CGGCGGTGGCGGT
• rs150026164
• NM_000427.3:c.69_80dupTGGCGGTGGCGG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM4 BP6_Moderate BS2

The NM_000427.3(LORICRIN):​c.69_80dupTGGCGGTGGCGG​(p.Gly24_Gly27dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,572,620 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00068 (1 hom., cov: 24)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: LORICRIN NM_000427.3 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.56
• Publications: 6 publications found

Genes affected

LORICRIN (HGNC:6663): (loricrin cornified envelope precursor protein) This gene encodes loricrin, a major protein component of the cornified cell envelope found in terminally differentiated epidermal cells. Mutations in this gene are associated with Vohwinkel's syndrome and progressive symmetric erythrokeratoderma, both inherited skin diseases. [provided by RefSeq, Jul 2008]

LORICRIN Gene-Disease associations (from GenCC):

• loricrin keratoderma

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000301414 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000427.3.
• BP6: Variant 1-153261012-C-CGGCGGTGGCGGT is Benign according to our data. Variant chr1-153261012-C-CGGCGGTGGCGGT is described in ClinVar as Likely_benign. ClinVar VariationId is 2081646.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 103 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000427.3. 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
	LORICRIN	NM_000427.3	MANE Select	c.69_80dupTGGCGGTGGCGG	p.Gly24_Gly27dup	disruptive_inframe_insertion	Exon 2 of 2	NP_000418.2	P23490

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LORICRIN	ENST00000368742.4	TSL:1 MANE Select	c.69_80dupTGGCGGTGGCGG	p.Gly24_Gly27dup	disruptive_inframe_insertion	Exon 2 of 2	ENSP00000357731.3	P23490
	ENSG00000301414	ENST00000778757.1		n.203+143_203+154dupTGGCGGTGGCGG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000680 AC: 103 AN: 151414 Hom.: 1 Cov.: 24

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000159 AC: 33 AN: 207700 AF XY: 0.000190

Gnomad AFR exome AF: 0.00180

Gnomad AMR exome AF: 0.000100

Gnomad ASJ exome AF: 0.000224

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000876

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000999 AC: 142 AN: 1421092 Hom.: 0 Cov.: 32 AF XY: 0.000102 AC XY: 72 AN XY: 706506

African (AFR) AF: 0.00225 AC: 68 AN: 30258

American (AMR) AF: 0.0000728 AC: 3 AN: 41196

Ashkenazi Jewish (ASJ) AF: 0.000239 AC: 6 AN: 25098

East Asian (EAS) AF: 0.00 AC: 0 AN: 36476

South Asian (SAS) AF: 0.0000728 AC: 6 AN: 82372

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50782

Middle Eastern (MID) AF: 0.000529 AC: 3 AN: 5668

European-Non Finnish (NFE) AF: 0.0000431 AC: 47 AN: 1090596

Other (OTH) AF: 0.000153 AC: 9 AN: 58646

GnomAD4 genome AF: 0.000680 AC: 103 AN: 151528 Hom.: 1 Cov.: 24 AF XY: 0.000635 AC XY: 47 AN XY: 74038

African (AFR) AF: 0.00216 AC: 89 AN: 41180

American (AMR) AF: 0.000197 AC: 3 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67836

Other (OTH) AF: 0.00143 AC: 3 AN: 2102

Alfa AF: 0.0000983 Hom.: 291

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6
Mutation Taster		=90/10	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs150026164; hg19: chr1-153233488;