1-152311948-G-T

Variant names:

• chr1-152311948-G-T
• rs12756586
• NM_002016.2:c.2938C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002016.2(FLG):​c.2938C>A​(p.His980Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,595,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H980D) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: FLG NM_002016.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.19

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]

FLG-AS1 (HGNC:):

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

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.00692755).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLG	NM_002016.2	c.2938C>A	p.His980Asn	missense_variant	Exon 3 of 3	ENST00000368799.2	NP_002007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLG	ENST00000368799.2	c.2938C>A	p.His980Asn	missense_variant	Exon 3 of 3	1	NM_002016.2	ENSP00000357789.1

Frequencies

GnomAD3 genomes AF: 0.000612 AC: 87 AN: 142148 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000141

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: 0.00

Gnomad OTH AF: 0.000510

GnomAD3 exomes AF: 0.000120 AC: 30 AN: 249840 Hom.: 0 AF XY: 0.000104 AC XY: 14 AN XY: 135198

Gnomad AFR exome AF: 0.00187

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000557 AC: 81 AN: 1453758 Hom.: 0 Cov.: 114 AF XY: 0.0000401 AC XY: 29 AN XY: 723278

Gnomad4 AFR exome AF: 0.00231

Gnomad4 AMR exome AF: 0.0000455

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000100

GnomAD4 genome AF: 0.000612 AC: 87 AN: 142236 Hom.: 0 Cov.: 30 AF XY: 0.000607 AC XY: 42 AN XY: 69216

Gnomad4 AFR AF: 0.00233

Gnomad4 AMR AF: 0.000141

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000505

Alfa AF: 0.0000744 Hom.: 2

ExAC AF: 0.000189 AC: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.0030
DANN	Benign	0.49
DEOGEN2	Benign	0.042	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.025
Sift	Benign	0.22	T
Polyphen		0.0090	B
Vest4		0.067
MVP		0.085
ClinPred		0.010	T
GERP RS		-6.6
Varity_R		0.039
gMVP		0.0064

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

Publications

LitVar

Other links and lift over

dbSNP: rs12756586; hg19: chr1-152284424;