1-152304869-C-T

Variant names:

• chr1-152304869-C-T
• rs2065956
• NM_002016.2:c.10017G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_002016.2(FLG):​c.10017G>A​(p.Gln3339Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,613,646 control chromosomes in the GnomAD database, including 33,854 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (3149 hom., cov: 29)
  • Exomes 𝑓: 0.17 (30705 hom.)
• Consequence: FLG NM_002016.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.308
• Publications: 20 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-152304869-C-T is Benign according to our data. Variant chr1-152304869-C-T is described in ClinVar as Benign. ClinVar VariationId is 2585647.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.308 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLG	NM_002016.2	MANE Select	c.10017G>A	p.Gln3339Gln	synonymous	Exon 3 of 3	NP_002007.1
	CCDST	NR_186761.1		n.578-27714C>T		intron	N/A
	CCDST	NR_186762.1		n.180-27714C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLG	ENST00000368799.2	TSL:1 MANE Select	c.10017G>A	p.Gln3339Gln	synonymous	Exon 3 of 3	ENSP00000357789.1
	CCDST	ENST00000420707.5	TSL:5	n.462+3036C>T		intron	N/A
	CCDST	ENST00000593011.5	TSL:4	n.376+3036C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23751 AN: 151688 Hom.: 3146 Cov.: 29

Gnomad AFR AF: 0.0340

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.292

Gnomad EAS AF: 0.567

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.195

GnomAD2 exomes AF: 0.243 AC: 61072 AN: 251484 AF XY: 0.243

Gnomad AFR exome AF: 0.0290

Gnomad AMR exome AF: 0.429

Gnomad ASJ exome AF: 0.281

Gnomad EAS exome AF: 0.560

Gnomad FIN exome AF: 0.171

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.228

GnomAD4 exome AF: 0.173 AC: 253172 AN: 1461840 Hom.: 30705 Cov.: 37 AF XY: 0.178 AC XY: 129525 AN XY: 727218

African (AFR) AF: 0.0265 AC: 888 AN: 33480

American (AMR) AF: 0.418 AC: 18697 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 7314 AN: 26136

East Asian (EAS) AF: 0.560 AC: 22219 AN: 39700

South Asian (SAS) AF: 0.359 AC: 30967 AN: 86236

European-Finnish (FIN) AF: 0.168 AC: 8970 AN: 53420

Middle Eastern (MID) AF: 0.250 AC: 1440 AN: 5766

European-Non Finnish (NFE) AF: 0.135 AC: 150220 AN: 1111990

Other (OTH) AF: 0.206 AC: 12457 AN: 60388

GnomAD4 genome AF: 0.156 AC: 23751 AN: 151806 Hom.: 3149 Cov.: 29 AF XY: 0.168 AC XY: 12443 AN XY: 74136

African (AFR) AF: 0.0339 AC: 1408 AN: 41500

American (AMR) AF: 0.327 AC: 4987 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 1013 AN: 3468

East Asian (EAS) AF: 0.566 AC: 2857 AN: 5048

South Asian (SAS) AF: 0.377 AC: 1795 AN: 4758

European-Finnish (FIN) AF: 0.178 AC: 1872 AN: 10518

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9204 AN: 67956

Other (OTH) AF: 0.192 AC: 405 AN: 2106

Alfa AF: 0.141 Hom.: 887

Bravo AF: 0.166

Asia WGS AF: 0.455 AC: 1579 AN: 3476

EpiCase AF: 0.151

EpiControl AF: 0.148

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ichthyosis vulgaris Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.37
DANN	Benign	0.32
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

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: rs2065956; hg19: chr1-152277345; COSMIC: COSV64237848;