rs2184953

Variant names:

• chr1-152308306-A-G
• rs2184953
• NM_002016.2:c.6580T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002016.2(FLG):​c.6580T>C​(p.Tyr2194His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,613,226 control chromosomes in the GnomAD database, including 63,839 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (14590 hom., cov: 32)
  • Exomes 𝑓: 0.22 (49249 hom.)
• Consequence: FLG NM_002016.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -5.55
• Publications: 34 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=1.5873069E-6).
• BP6: Variant 1-152308306-A-G is Benign according to our data. Variant chr1-152308306-A-G is described in ClinVar as Benign. ClinVar VariationId is 1244740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.695 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.6580T>C	p.Tyr2194His	missense	Exon 3 of 3	NP_002007.1
	CCDST	NR_186761.1		n.578-24277A>G		intron	N/A
	CCDST	NR_186762.1		n.180-24277A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLG	ENST00000368799.2	TSL:1 MANE Select	c.6580T>C	p.Tyr2194His	missense	Exon 3 of 3	ENSP00000357789.1
	CCDST	ENST00000420707.5	TSL:5	n.462+6473A>G		intron	N/A
	CCDST	ENST00000593011.5	TSL:4	n.376+6473A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.370 AC: 55897 AN: 151236 Hom.: 14547 Cov.: 32

Gnomad AFR AF: 0.701

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.633

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.352

GnomAD2 exomes AF: 0.319 AC: 80243 AN: 251412 AF XY: 0.308

Gnomad AFR exome AF: 0.717

Gnomad AMR exome AF: 0.476

Gnomad ASJ exome AF: 0.314

Gnomad EAS exome AF: 0.605

Gnomad FIN exome AF: 0.179

Gnomad NFE exome AF: 0.168

Gnomad OTH exome AF: 0.279

GnomAD4 exome AF: 0.219 AC: 320538 AN: 1461870 Hom.: 49249 Cov.: 123 AF XY: 0.222 AC XY: 161774 AN XY: 727234

African (AFR) AF: 0.715 AC: 23926 AN: 33480

American (AMR) AF: 0.470 AC: 21022 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 8150 AN: 26136

East Asian (EAS) AF: 0.620 AC: 24613 AN: 39696

South Asian (SAS) AF: 0.418 AC: 36050 AN: 86258

European-Finnish (FIN) AF: 0.177 AC: 9445 AN: 53416

Middle Eastern (MID) AF: 0.325 AC: 1872 AN: 5768

European-Non Finnish (NFE) AF: 0.161 AC: 178676 AN: 1112000

Other (OTH) AF: 0.278 AC: 16784 AN: 60396

GnomAD4 genome AF: 0.370 AC: 55989 AN: 151356 Hom.: 14590 Cov.: 32 AF XY: 0.376 AC XY: 27816 AN XY: 73884

African (AFR) AF: 0.702 AC: 29008 AN: 41344

American (AMR) AF: 0.423 AC: 6433 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 1121 AN: 3466

East Asian (EAS) AF: 0.632 AC: 3258 AN: 5152

South Asian (SAS) AF: 0.452 AC: 2166 AN: 4796

European-Finnish (FIN) AF: 0.193 AC: 1989 AN: 10332

Middle Eastern (MID) AF: 0.315 AC: 92 AN: 292

European-Non Finnish (NFE) AF: 0.163 AC: 11017 AN: 67750

Other (OTH) AF: 0.347 AC: 726 AN: 2092

Alfa AF: 0.241 Hom.: 17386

Bravo AF: 0.400

TwinsUK AF: 0.161 AC: 598

ALSPAC AF: 0.165 AC: 635

ExAC AF: 0.317 AC: 38520

EpiCase AF: 0.179

EpiControl AF: 0.176

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Ichthyosis vulgaris (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.097
DANN	Benign	0.33
DEOGEN2	Benign	0.021	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0000016	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		-5.6
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.59	N
REVEL	Benign	0.0070
Sift	Benign	0.48	T
Polyphen		0.0030	B
Vest4		0.046
ClinPred		0.0026	T
GERP RS		-6.0
Varity_R		0.031
gMVP		0.034
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: rs2184953; hg19: chr1-152280782; COSMIC: COSV64235971;