chr1-152351142-C-T

Variant names:

• chr1-152351142-C-T
• rs755839824
• NM_001014342.3:c.6644G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001014342.3(FLG2):​c.6644G>A​(p.Gly2215Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,609,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: FLG2 NM_001014342.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -9.26
• Publications: 0 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04335639).
• BP6: Variant 1-152351142-C-T is Benign according to our data. Variant chr1-152351142-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2639329.

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.6644G>A	p.Gly2215Asp	missense	Exon 3 of 3	NP_001014364.1	Q5D862
	CCDST	NR_103778.1		n.1406+9932C>T		intron	N/A
	CCDST	NR_103779.1		n.151+9932C>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.6644G>A	p.Gly2215Asp	missense	Exon 3 of 3	ENSP00000373370.4	Q5D862
	CCDST	ENST00000445097.2	TSL:1	n.151+9932C>T		intron	N/A
	CCDST	ENST00000392688.7	TSL:2	n.1406+9932C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000136 AC: 2 AN: 147394 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000410

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251152 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461842 Hom.: 0 Cov.: 36 AF XY: 0.00000825 AC XY: 6 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111974

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome AF: 0.0000136 AC: 2 AN: 147394 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 71904

African (AFR) AF: 0.00 AC: 0 AN: 39626

American (AMR) AF: 0.00 AC: 0 AN: 14838

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.000410 AC: 2 AN: 4878

South Asian (SAS) AF: 0.00 AC: 0 AN: 4614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66646

Other (OTH) AF: 0.00 AC: 0 AN: 2002

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.0030
DANN	Benign	0.51
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.55	N
PhyloP100		-9.3
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.10
Sift	Benign	0.60	T
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.12
MutPred		0.22		Loss of glycosylation at S2214 (P = 0.0254)
MVP		0.040
MPC		0.14
ClinPred		0.39	T
GERP RS		-7.1
Varity_R		0.048
gMVP		0.022
Mutation Taster		=97/3	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: rs755839824; hg19: chr1-152323618;