NM_002016.2:c.1236T>C

Variant names:

• chr1-152313650-A-G
• rs11582620
• NM_002016.2:c.1236T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002016.2(FLG):​c.1236T>C​(p.Arg412Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,613,394 control chromosomes in the GnomAD database, including 12,680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.091 (912 hom., cov: 31)
  • Exomes 𝑓: 0.12 (11768 hom.)
• Consequence: FLG NM_002016.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.63
• Publications: 19 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-152313650-A-G is Benign according to our data. Variant chr1-152313650-A-G is described in ClinVar as Benign. ClinVar VariationId is 1259919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.63 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.187 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.1236T>C	p.Arg412Arg	synonymous	Exon 3 of 3	NP_002007.1
	CCDST	NR_103778.1		n.192A>G		non_coding_transcript_exon	Exon 1 of 7
	CCDST	NR_186761.1		n.578-18933A>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.1236T>C	p.Arg412Arg	synonymous	Exon 3 of 3	ENSP00000357789.1
	CCDST	ENST00000392688.7	TSL:2	n.192A>G		non_coding_transcript_exon	Exon 1 of 7
	CCDST	ENST00000665223.1		n.1075A>G		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.0914 AC: 13834 AN: 151386 Hom.: 914 Cov.: 31

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.0786

Gnomad ASJ AF: 0.0646

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.0871

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.0805

GnomAD2 exomes AF: 0.116 AC: 29148 AN: 251476 AF XY: 0.122

Gnomad AFR exome AF: 0.0178

Gnomad AMR exome AF: 0.0931

Gnomad ASJ exome AF: 0.0614

Gnomad EAS exome AF: 0.102

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.119

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.122 AC: 178877 AN: 1461886 Hom.: 11768 Cov.: 72 AF XY: 0.125 AC XY: 91264 AN XY: 727246

African (AFR) AF: 0.0160 AC: 536 AN: 33480

American (AMR) AF: 0.0893 AC: 3993 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0656 AC: 1715 AN: 26136

East Asian (EAS) AF: 0.118 AC: 4695 AN: 39700

South Asian (SAS) AF: 0.208 AC: 17919 AN: 86258

European-Finnish (FIN) AF: 0.128 AC: 6855 AN: 53418

Middle Eastern (MID) AF: 0.0990 AC: 571 AN: 5768

European-Non Finnish (NFE) AF: 0.122 AC: 135853 AN: 1112006

Other (OTH) AF: 0.112 AC: 6740 AN: 60396

GnomAD4 genome AF: 0.0913 AC: 13830 AN: 151508 Hom.: 912 Cov.: 31 AF XY: 0.0932 AC XY: 6893 AN XY: 73998

African (AFR) AF: 0.0213 AC: 880 AN: 41298

American (AMR) AF: 0.0787 AC: 1198 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.0646 AC: 224 AN: 3468

East Asian (EAS) AF: 0.101 AC: 507 AN: 5040

South Asian (SAS) AF: 0.198 AC: 941 AN: 4760

European-Finnish (FIN) AF: 0.130 AC: 1371 AN: 10518

Middle Eastern (MID) AF: 0.0862 AC: 25 AN: 290

European-Non Finnish (NFE) AF: 0.124 AC: 8387 AN: 67884

Other (OTH) AF: 0.0787 AC: 166 AN: 2108

Alfa AF: 0.108 Hom.: 1876

Bravo AF: 0.0825

Asia WGS AF: 0.117 AC: 407 AN: 3478

EpiCase AF: 0.122

EpiControl AF: 0.115

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	FLG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.1
DANN	Benign	0.46
PhyloP100		-4.6
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: rs11582620; hg19: chr1-152286126; COSMIC: COSV64236548;