1-152302796-C-T

Variant names:

• chr1-152302796-C-T
• rs117440780
• NM_002016.2:c.12090G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2_Supporting

The NM_002016.2(FLG):​c.12090G>A​(p.Thr4030Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,614,142 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (45 hom.)
• Consequence: FLG NM_002016.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.76
• Publications: 4 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-152302796-C-T is Benign according to our data. Variant chr1-152302796-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1211343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.76 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00237 (361/152268) while in subpopulation EAS AF = 0.0268 (139/5186). AF 95% confidence interval is 0.0232. There are 7 homozygotes in GnomAd4. There are 182 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 SD,XL,AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.12090G>A	p.Thr4030Thr	synonymous	Exon 3 of 3	NP_002007.1	P20930
	CCDST	NR_186761.1		n.578-29787C>T		intron	N/A
	CCDST	NR_186762.1		n.180-29787C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLG	ENST00000368799.2	TSL:1 MANE Select	c.12090G>A	p.Thr4030Thr	synonymous	Exon 3 of 3	ENSP00000357789.1	P20930
	CCDST	ENST00000420707.5	TSL:5	n.462+963C>T		intron	N/A
	CCDST	ENST00000593011.5	TSL:4	n.376+963C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 357 AN: 152150 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00333

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.0267

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00329 AC: 828 AN: 251330 AF XY: 0.00293

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00437

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.0298

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00155 AC: 2262 AN: 1461874 Hom.: 45 Cov.: 31 AF XY: 0.00149 AC XY: 1080 AN XY: 727238

African (AFR) AF: 0.00323 AC: 108 AN: 33480

American (AMR) AF: 0.00398 AC: 178 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00241 AC: 63 AN: 26136

East Asian (EAS) AF: 0.0402 AC: 1597 AN: 39700

South Asian (SAS) AF: 0.000568 AC: 49 AN: 86256

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53412

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000157 AC: 175 AN: 1112008

Other (OTH) AF: 0.00132 AC: 80 AN: 60392

GnomAD4 genome AF: 0.00237 AC: 361 AN: 152268 Hom.: 7 Cov.: 31 AF XY: 0.00244 AC XY: 182 AN XY: 74450

African (AFR) AF: 0.00335 AC: 139 AN: 41552

American (AMR) AF: 0.00373 AC: 57 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.0268 AC: 139 AN: 5186

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00125 Hom.: 7

Bravo AF: 0.00284

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	FLG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.34
DANN	Benign	0.64
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism

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: rs117440780; hg19: chr1-152275272; COSMIC: COSV64238804;