NM_000427.3:c.75_80dupTGGCGG

Variant names:

• chr1-153261012-C-CGGCGGT
• rs150026164
• NM_000427.3:c.75_80dupTGGCGG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM4 BP6_Moderate BA1

The NM_000427.3(LORICRIN):​c.75_80dupTGGCGG​(p.Gly26_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 0.203 in 1,571,718 control chromosomes in the GnomAD database, including 35,515 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (4988 hom., cov: 24)
  • Exomes 𝑓: 0.20 (30527 hom.)
• Consequence: LORICRIN NM_000427.3 disruptive_inframe_insertion
• Clinical Significance: 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: Benign. The variant received -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000427.3.
• BP6: Variant 1-153261012-C-CGGCGGT is Benign according to our data. Variant chr1-153261012-C-CGGCGGT is described in ClinVar as Benign. ClinVar VariationId is 2002883.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

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.75_80dupTGGCGG	p.Gly26_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.75_80dupTGGCGG	p.Gly26_Gly27dup	disruptive_inframe_insertion	Exon 2 of 2	ENSP00000357731.3	P23490
	ENSG00000301414	ENST00000778757.1		n.203+149_203+154dupTGGCGG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36508 AN: 151280 Hom.: 4991 Cov.: 24

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.369

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.0773

Gnomad SAS AF: 0.0630

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.205

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.211

GnomAD2 exomes AF: 0.166 AC: 34460 AN: 207700 AF XY: 0.163

Gnomad AFR exome AF: 0.349

Gnomad AMR exome AF: 0.0919

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.0779

Gnomad FIN exome AF: 0.211

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.199 AC: 282161 AN: 1420324 Hom.: 30527 Cov.: 32 AF XY: 0.195 AC XY: 137356 AN XY: 706106

African (AFR) AF: 0.384 AC: 11615 AN: 30240

American (AMR) AF: 0.108 AC: 4442 AN: 41164

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 4231 AN: 25082

East Asian (EAS) AF: 0.0616 AC: 2247 AN: 36464

South Asian (SAS) AF: 0.0629 AC: 5181 AN: 82324

European-Finnish (FIN) AF: 0.214 AC: 10831 AN: 50716

Middle Eastern (MID) AF: 0.244 AC: 1380 AN: 5656

European-Non Finnish (NFE) AF: 0.212 AC: 230698 AN: 1090060

Other (OTH) AF: 0.197 AC: 11536 AN: 58618

GnomAD4 genome AF: 0.241 AC: 36530 AN: 151394 Hom.: 4988 Cov.: 24 AF XY: 0.236 AC XY: 17442 AN XY: 73978

African (AFR) AF: 0.375 AC: 15430 AN: 41112

American (AMR) AF: 0.169 AC: 2572 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 619 AN: 3466

East Asian (EAS) AF: 0.0769 AC: 397 AN: 5160

South Asian (SAS) AF: 0.0637 AC: 306 AN: 4806

European-Finnish (FIN) AF: 0.222 AC: 2333 AN: 10506

Middle Eastern (MID) AF: 0.184 AC: 53 AN: 288

European-Non Finnish (NFE) AF: 0.207 AC: 14041 AN: 67794

Other (OTH) AF: 0.213 AC: 446 AN: 2098

Alfa AF: 0.125 Hom.: 291

Asia WGS AF: 0.0920 AC: 317 AN: 3478

ClinVar

ClinVar submissions

Significance: 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 (auto)

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; COSMIC: COSV64201243;