rs149503979

Variant names:

• chr1-152351362-C-T
• rs149503979
• NM_001014342.3:c.6424G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001014342.3(FLG2):​c.6424G>A​(p.Gly2142Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000347 in 1,613,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: FLG2 NM_001014342.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.02
• Publications: 4 publications found

Genes affected

FLG2 (HGNC:33276): (filaggrin 2) The filaggrin-like protein encoded by this gene is upregulated by calcium, proteolyzed by calpain 1, and is involved in epithelial homeostasis. The encoded protein is required for proper cornification in skin, with defects in this gene being associated with skin diseases. This protein also has a function in skin barrier protection. In fact, in addition to providing a physical barrier, C-terminal fragments of this protein display antimicrobial activity against P. aeruginosa and E. coli. [provided by RefSeq, Jul 2020]

CCDST (HGNC:55988): (cervical cancer associated DHX9 suppressive transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013088703).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001014342.3. 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
	FLG2	NM_001014342.3	MANE Select	c.6424G>A	p.Gly2142Arg	missense	Exon 3 of 3	NP_001014364.1	Q5D862
	CCDST	NR_103778.1		n.1406+10152C>T		intron	N/A
	CCDST	NR_103779.1		n.151+10152C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLG2	ENST00000388718.5	TSL:5 MANE Select	c.6424G>A	p.Gly2142Arg	missense	Exon 3 of 3	ENSP00000373370.4	Q5D862
	CCDST	ENST00000445097.2	TSL:1	n.151+10152C>T		intron	N/A
	CCDST	ENST00000392688.7	TSL:2	n.1406+10152C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 151592 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000526

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000497 AC: 125 AN: 251440 AF XY: 0.000346

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000360 AC: 526 AN: 1461876 Hom.: 0 Cov.: 36 AF XY: 0.000327 AC XY: 238 AN XY: 727240

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00195 AC: 87 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86256

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000365 AC: 406 AN: 1112006

Other (OTH) AF: 0.000248 AC: 15 AN: 60392

GnomAD4 genome AF: 0.000224 AC: 34 AN: 151592 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 73992

African (AFR) AF: 0.0000243 AC: 1 AN: 41214

American (AMR) AF: 0.000526 AC: 8 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 67942

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.000249

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000453 AC: 55

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.76
DANN	Benign	0.48
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L
PhyloP100		-2.0
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.023
Sift	Benign	0.10	T
Sift4G	Uncertain	0.057	T
Polyphen		0.79	P
Vest4		0.21
MutPred		0.37		Gain of MoRF binding (P = 0.0124)
MVP		0.13
MPC		0.047
ClinPred		0.042	T
GERP RS		-0.20
Varity_R		0.13
gMVP		0.013
Mutation Taster		=99/1	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: rs149503979; hg19: chr1-152323838; COSMIC: COSV101166296;