rs558269137

Variant names:

• chr1-152312600-CACTG-C
• rs558269137
• NM_002016.2:c.2282_2285delCAGT

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PS3 PP5

The NM_002016.2(FLG):​c.2282_2285delCAGT​(p.Ser761CysfsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 151,974 control chromosomes in the GnomAD database, including 18 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000712217: Patients homozygous for this variant had absent filaggrin by biochemical analysis (Smith 2006)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.013 (18 hom., cov: 29)
  • Exomes 𝑓: 0.020 (396 hom.)
  • Failed GnomAD Quality Control
• Consequence: FLG NM_002016.2 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:47 U:1 O:2
• Conservation: PhyloP100: 0.419
• Publications: 51 publications found

Genes affected

FLG (HGNC:3748): (filaggrin) The protein encoded by this gene is an intermediate filament-associated protein that aggregates keratin intermediate filaments in mammalian epidermis. It is initially synthesized as a polyprotein precursor, profilaggrin (consisting of multiple filaggrin units of 324 aa each), which is localized in keratohyalin granules, and is subsequently proteolytically processed into individual functional filaggrin molecules. Mutations in this gene are associated with ichthyosis vulgaris.[provided by RefSeq, Dec 2009]

CCDST (HGNC:55988): (cervical cancer associated DHX9 suppressive transcript)

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 203 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000712217: Patients homozygous for this variant had absent filaggrin by biochemical analysis (Smith 2006).; SCV000321673: Results in a functional null allele as no processed filaggrin can be biochemically detected in patients with this variant (Smith et al., 2006);; SCV001552929: "Additionally, functional analysis has demonstrated that this variant results in loss of filaggrin production and impaired epidermal barrier formation (Smith_2006_PMID:16444271)."; SCV000804438: The c.2282_2285delCAGT variant is a functional null allele as no processed filaggrin can be biochemically detected in patients with this variant (Smith et al., 2006).; SCV004046166: Functional studies have confirmed this variant leads to loss of filaggrin protein production (PMID: 16444271).; SCV004104648: Functional studies indicate that this sequence variant results in complete absence of the functionally important filaggrin peptide (Smith et al. 2006. PubMed ID: 16444271).; SCV005398584: "Strong functional evidence supporting abnormal protein function. A complete loss of filaggrin peptide production was observed by immunohistochemistry in a skin biopsy from a patient." PMID:16444271
• PP5: Variant 1-152312600-CACTG-C is Pathogenic according to our data. Variant chr1-152312600-CACTG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 16320.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002016.2. 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
	FLG	NM_002016.2	MANE Select	c.2282_2285delCAGT	p.Ser761CysfsTer36	frameshift	Exon 3 of 3	NP_002007.1	P20930
	CCDST	NR_186761.1		n.578-19978_578-19975delACTG		intron	N/A
	CCDST	NR_186762.1		n.180-19978_180-19975delACTG		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLG	ENST00000368799.2	TSL:1 MANE Select	c.2282_2285delCAGT	p.Ser761CysfsTer36	frameshift	Exon 3 of 3	ENSP00000357789.1	P20930
	CCDST	ENST00000665223.1		n.30_33delACTG		non_coding_transcript_exon	Exon 1 of 5
	CCDST	ENST00000420707.5	TSL:5	n.463-2301_463-2298delACTG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1913 AN: 151856 Hom.: 18 Cov.: 29

Gnomad AFR AF: 0.00378

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00831

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0219

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.0129 AC: 3237 AN: 251484 AF XY: 0.0128

Gnomad AFR exome AF: 0.00338

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00754

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0149

Gnomad NFE exome AF: 0.0213

Gnomad OTH exome AF: 0.0135

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0196 AC: 28705 AN: 1461820 Hom.: 396 AF XY: 0.0191 AC XY: 13885 AN XY: 727210

African (AFR) AF: 0.00335 AC: 112 AN: 33478

American (AMR) AF: 0.00186 AC: 83 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00773 AC: 202 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.00779 AC: 672 AN: 86244

European-Finnish (FIN) AF: 0.0145 AC: 777 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0234 AC: 26005 AN: 1111980

Other (OTH) AF: 0.0141 AC: 851 AN: 60396

GnomAD4 genome AF: 0.0126 AC: 1913 AN: 151974 Hom.: 18 Cov.: 29 AF XY: 0.0116 AC XY: 865 AN XY: 74280

African (AFR) AF: 0.00377 AC: 156 AN: 41394

American (AMR) AF: 0.00367 AC: 56 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00577 AC: 20 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00832 AC: 40 AN: 4808

European-Finnish (FIN) AF: 0.0132 AC: 140 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0219 AC: 1488 AN: 67994

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.0173 Hom.: 10

Bravo AF: 0.0116

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0182

EpiControl AF: 0.0197

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
23	-	-	Ichthyosis vulgaris (23)
10	-	-	not provided (10)
3	1	-	Ichthyosis vulgaris;C1853965:Dermatitis, atopic, 2 (4)
2	-	-	Dermatitis, atopic, 2 (2)
2	-	-	FLG-related disorder (3)
1	-	-	Autosomal dominant ichthyosis vulgaris (1)
1	-	-	Autosomal recessive congenital ichthyosis (1)
1	-	-	Autosomal recessive nonsyndromic hearing loss 1A (1)
1	-	-	Eczematoid dermatitis (1)
1	-	-	Ichthyosis and erythrokeratoderma (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Palmoplantar keratodermas (1)
-	-	-	Dermatitis, atopic, 2, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.42
Mutation Taster		=10/190	disease causing (ClinVar)

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: rs558269137; hg19: chr1-152285076; COSMIC: COSV64238631; COSMIC: COSV64238631;