NM_002016.2:c.11909C>T

Variant names:

• chr1-152302977-G-A
• rs3814299
• NM_002016.2:c.11909C>T

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.11909C>T​(p.Ser3970Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00654 in 1,614,126 control chromosomes in the GnomAD database, including 491 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 0.012 (86 hom., cov: 31)
  • Exomes 𝑓: 0.0059 (405 hom.)
• Consequence: FLG NM_002016.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.90
• Publications: 9 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=0.0020753741).
• BP6: Variant 1-152302977-G-A is Benign according to our data. Variant chr1-152302977-G-A is described in ClinVar as Benign. ClinVar VariationId is 1231239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0838 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLG	NM_002016.2	MANE Select	c.11909C>T	p.Ser3970Leu	missense	Exon 3 of 3	NP_002007.1	P20930
	CCDST	NR_186761.1		n.578-29606G>A		intron	N/A
	CCDST	NR_186762.1		n.180-29606G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLG	ENST00000368799.2	TSL:1 MANE Select	c.11909C>T	p.Ser3970Leu	missense	Exon 3 of 3	ENSP00000357789.1	P20930
	CCDST	ENST00000420707.5	TSL:5	n.462+1144G>A		intron	N/A
	CCDST	ENST00000593011.5	TSL:4	n.376+1144G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1871 AN: 152130 Hom.: 83 Cov.: 31

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0871

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.0627

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.0211 AC: 5302 AN: 251374 AF XY: 0.0170

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.00923

Gnomad EAS exome AF: 0.0602

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.0160

GnomAD4 exome AF: 0.00594 AC: 8687 AN: 1461878 Hom.: 405 Cov.: 31 AF XY: 0.00540 AC XY: 3927 AN XY: 727238

African (AFR) AF: 0.00143 AC: 48 AN: 33480

American (AMR) AF: 0.111 AC: 4947 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00819 AC: 214 AN: 26136

East Asian (EAS) AF: 0.0658 AC: 2614 AN: 39700

South Asian (SAS) AF: 0.00174 AC: 150 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.000218 AC: 242 AN: 1112004

Other (OTH) AF: 0.00775 AC: 468 AN: 60396

GnomAD4 genome AF: 0.0123 AC: 1875 AN: 152248 Hom.: 86 Cov.: 31 AF XY: 0.0145 AC XY: 1082 AN XY: 74450

African (AFR) AF: 0.00258 AC: 107 AN: 41546

American (AMR) AF: 0.0877 AC: 1341 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00779 AC: 27 AN: 3468

East Asian (EAS) AF: 0.0620 AC: 321 AN: 5174

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68018

Other (OTH) AF: 0.0165 AC: 35 AN: 2116

Alfa AF: 0.00672 Hom.: 111

Bravo AF: 0.0178

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.0160 AC: 1945

Asia WGS AF: 0.0360 AC: 124 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000889

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.49
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.9
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.068
Sift	Uncertain	0.0020	D
Polyphen		0.90	P
Vest4		0.11
ClinPred		0.019	T
GERP RS		2.2
Varity_R		0.049
gMVP		0.0060
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: rs3814299; hg19: chr1-152275453; COSMIC: COSV64242993;