19-42387387-C-A

Position:

• chr19-42387387-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032488.4(CNFN):​c.202G>T​(p.Gly68Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CNFN NM_032488.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39

Genes affected

CNFN (HGNC:30183): (cornifelin) Predicted to be involved in keratinization. Located in cornified envelope. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNFN	NM_032488.4	c.202G>T	p.Gly68Cys	missense_variant	3/4	ENST00000222032.10	NP_115877.2
CNFN	XM_005259332.4	c.241G>T	p.Gly81Cys	missense_variant	4/5		XP_005259389.1
CNFN	XM_011527396.3	c.241G>T	p.Gly81Cys	missense_variant	4/5		XP_011525698.1
CNFN	XM_011527397.3	c.241G>T	p.Gly81Cys	missense_variant	4/5		XP_011525699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNFN	ENST00000222032.10	c.202G>T	p.Gly68Cys	missense_variant	3/4	1	NM_032488.4	ENSP00000222032.4
CNFN	ENST00000597255.1	c.202G>T	p.Gly68Cys	missense_variant	4/5	1		ENSP00000469590.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1448972 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 719960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2024

The c.202G>T (p.G68C) alteration is located in exon 3 (coding exon 2) of the CNFN gene. This alteration results from a G to T substitution at nucleotide position 202, causing the glycine (G) at amino acid position 68 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.050	T;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.67	.;T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	-0.49	N;N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.92	N;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.015	D;.
Sift4G	Benign	0.15	T;T
Polyphen		1.0	D;D
Vest4		0.64
MutPred		0.48		Loss of disorder (P = 0.0463);Loss of disorder (P = 0.0463);
MVP		0.50
MPC		0.41
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.28
gMVP		0.67

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: rs2039859385; hg19: chr19-42891539;