chr1-152351220-T-G

Variant names:

• chr1-152351220-T-G
• rs187944122
• NM_001014342.3:c.6566A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001014342.3(FLG2):​c.6566A>C​(p.His2189Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,613,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: FLG2 NM_001014342.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.11
• Publications: 1 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.118671775).

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.6566A>C	p.His2189Pro	missense	Exon 3 of 3	NP_001014364.1	Q5D862
	CCDST	NR_103778.1		n.1406+10010T>G		intron	N/A
	CCDST	NR_103779.1		n.151+10010T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLG2	ENST00000388718.5	TSL:5 MANE Select	c.6566A>C	p.His2189Pro	missense	Exon 3 of 3	ENSP00000373370.4	Q5D862
	CCDST	ENST00000445097.2	TSL:1	n.151+10010T>G		intron	N/A
	CCDST	ENST00000392688.7	TSL:2	n.1406+10010T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000106 AC: 16 AN: 151318 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000389

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251288 AF XY: 0.00000736

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000150 AC: 22 AN: 1461884 Hom.: 0 Cov.: 36 AF XY: 0.00000550 AC XY: 4 AN XY: 727242

African (AFR) AF: 0.000627 AC: 21 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: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.000106 AC: 16 AN: 151436 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74030

African (AFR) AF: 0.000388 AC: 16 AN: 41232

American (AMR) AF: 0.00 AC: 0 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.00 AC: 0 AN: 4768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67820

Other (OTH) AF: 0.00 AC: 0 AN: 2100

Alfa AF: 0.000219 Hom.: 0

Bravo AF: 0.000178

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	15
DANN	Benign	0.78
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.1
PrimateAI	Benign	0.27	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.023
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.023	D
Polyphen		0.73	P
Vest4		0.30
MVP		0.31
MPC		0.22
ClinPred		0.28	T
GERP RS		3.2
Varity_R		0.60
gMVP		0.048
Mutation Taster		=87/13	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: rs187944122; hg19: chr1-152323696;