NM_001014342.3:c.6709T>C

Variant names:

• chr1-152351077-A-G
• rs772026240
• NM_001014342.3:c.6709T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001014342.3(FLG2):​c.6709T>C​(p.Tyr2237His) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FLG2 NM_001014342.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.369
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02417326).
• BP6: Variant 1-152351077-A-G is Benign according to our data. Variant chr1-152351077-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3279141.Status of the report is criteria_provided_single_submitter, 1 stars.

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.6709T>C	p.Tyr2237His	missense	Exon 3 of 3	NP_001014364.1	Q5D862
	CCDST	NR_103778.1		n.1406+9867A>G		intron	N/A
	CCDST	NR_103779.1		n.151+9867A>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.6709T>C	p.Tyr2237His	missense	Exon 3 of 3	ENSP00000373370.4	Q5D862
	CCDST	ENST00000445097.2	TSL:1	n.151+9867A>G		intron	N/A
	CCDST	ENST00000392688.7	TSL:2	n.1406+9867A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 145420 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: 0.00

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: 0.0000161 AC: 4 AN: 248398 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000120

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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000110 AC: 16 AN: 1460106 Hom.: 0 Cov.: 36 AF XY: 0.00000688 AC XY: 5 AN XY: 726340

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.000181 AC: 8 AN: 44286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 85950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111186

Other (OTH) AF: 0.0000166 AC: 1 AN: 60318

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000345008), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 145546 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 71268

African (AFR) AF: 0.00 AC: 0 AN: 39270

American (AMR) AF: 0.00 AC: 0 AN: 14760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3348

East Asian (EAS) AF: 0.00 AC: 0 AN: 4724

South Asian (SAS) AF: 0.00 AC: 0 AN: 4532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65596

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

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

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	0.17
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.12
DANN	Benign	0.59
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00098	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.2	N
PhyloP100		-0.37
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.020
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.024	B
Vest4		0.076
MutPred		0.20		Loss of phosphorylation at Y2237 (P = 0.0269)
MVP		0.11
MPC		0.029
ClinPred		0.051	T
GERP RS		0.53
Varity_R		0.030
gMVP		0.035
Mutation Taster		=100/0	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: rs772026240; hg19: chr1-152323553;