1-152310208-G-A

Variant names:

• chr1-152310208-G-A
• rs151103850
• NM_002016.2:c.4678C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002016.2(FLG):​c.4678C>T​(p.Arg1560Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0394 in 1,613,778 control chromosomes in the GnomAD database, including 1,536 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (104 hom., cov: 30)
  • Exomes 𝑓: 0.040 (1432 hom.)
• Consequence: FLG NM_002016.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.56
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029270947).
• BP6: Variant 1-152310208-G-A is Benign according to our data. Variant chr1-152310208-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 402868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0297 (4509/151892) while in subpopulation NFE AF = 0.0435 (2954/67960). AF 95% confidence interval is 0.0422. There are 104 homozygotes in GnomAd4. There are 2189 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 104 SD,XL,AR,AD gene

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.4678C>T	p.Arg1560Cys	missense	Exon 3 of 3	NP_002007.1
	CCDST	NR_186761.1		n.578-22375G>A		intron	N/A
	CCDST	NR_186762.1		n.180-22375G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLG	ENST00000368799.2	TSL:1 MANE Select	c.4678C>T	p.Arg1560Cys	missense	Exon 3 of 3	ENSP00000357789.1
	CCDST	ENST00000420707.5	TSL:5	n.463-4698G>A		intron	N/A
	CCDST	ENST00000593011.5	TSL:4	n.377-4698G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0297 AC: 4509 AN: 151774 Hom.: 104 Cov.: 30

Gnomad AFR AF: 0.00791

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.0242

Gnomad ASJ AF: 0.0622

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.0119

Gnomad FIN AF: 0.0486

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0435

Gnomad OTH AF: 0.0245

GnomAD2 exomes AF: 0.0310 AC: 7792 AN: 251470 AF XY: 0.0312

Gnomad AFR exome AF: 0.00621

Gnomad AMR exome AF: 0.0156

Gnomad ASJ exome AF: 0.0591

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0524

Gnomad NFE exome AF: 0.0427

Gnomad OTH exome AF: 0.0332

GnomAD4 exome AF: 0.0404 AC: 59123 AN: 1461886 Hom.: 1432 Cov.: 87 AF XY: 0.0398 AC XY: 28937 AN XY: 727244

African (AFR) AF: 0.00591 AC: 198 AN: 33480

American (AMR) AF: 0.0164 AC: 733 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0600 AC: 1569 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.0137 AC: 1186 AN: 86258

European-Finnish (FIN) AF: 0.0539 AC: 2877 AN: 53420

Middle Eastern (MID) AF: 0.00988 AC: 57 AN: 5768

European-Non Finnish (NFE) AF: 0.0452 AC: 50264 AN: 1112006

Other (OTH) AF: 0.0370 AC: 2234 AN: 60396

GnomAD4 genome AF: 0.0297 AC: 4509 AN: 151892 Hom.: 104 Cov.: 30 AF XY: 0.0295 AC XY: 2189 AN XY: 74220

African (AFR) AF: 0.00789 AC: 327 AN: 41452

American (AMR) AF: 0.0241 AC: 368 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.0622 AC: 216 AN: 3470

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5114

South Asian (SAS) AF: 0.0121 AC: 58 AN: 4800

European-Finnish (FIN) AF: 0.0486 AC: 513 AN: 10548

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0435 AC: 2954 AN: 67960

Other (OTH) AF: 0.0242 AC: 51 AN: 2104

Alfa AF: 0.0369 Hom.: 134

Bravo AF: 0.0268

TwinsUK AF: 0.0496 AC: 184

ALSPAC AF: 0.0475 AC: 183

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.0410 AC: 353

ExAC AF: 0.0307 AC: 3722

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0414

EpiControl AF: 0.0398

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ichthyosis vulgaris Benign:2

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 08, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

not provided Benign:2

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31482965)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		-2.6
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.084
Sift	Benign	0.068	T
Polyphen		0.98	D
Vest4		0.031
ClinPred		0.024	T
GERP RS		0.34
Varity_R		0.057
gMVP		0.020
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: rs151103850; hg19: chr1-152282684; COSMIC: COSV64241918; COSMIC: COSV64241918;