dbSNP rs2039859385: CNFN:p.Gly68Cys (chr19-42387387-C-A) – ACMG Classification: Uncertain_significance (2 pts)

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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CNFN
NM_032488.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.39

Variant links:

Genes affected

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

CNFN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
CNFN	NM_032488.4 link	c.202G>T	p.Gly68Cys	missense_variant	Exon 3 of 4	ENST00000222032.10	NP_115877.2	Q9BYD5
CNFN	XM_005259332.4 link	c.241G>T	p.Gly81Cys	missense_variant	Exon 4 of 5		XP_005259389.1
CNFN	XM_011527396.3 link	c.241G>T	p.Gly81Cys	missense_variant	Exon 4 of 5		XP_011525698.1
CNFN	XM_011527397.3 link	c.241G>T	p.Gly81Cys	missense_variant	Exon 4 of 5		XP_011525699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNFN	ENST00000222032.10 link	c.202G>T	p.Gly68Cys	missense_variant	Exon 3 of 4	1	NM_032488.4	ENSP00000222032.4		Q9BYD5
CNFN	ENST00000597255.1 link	c.202G>T	p.Gly68Cys	missense_variant	Exon 4 of 5	1		ENSP00000469590.1		Q9BYD5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1448972

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.050

T;T

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.67

.;T

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.60

D;D

MetaSVM

Benign

-0.77

MutationAssessor

Benign

-0.49

N;N

PrimateAI

Pathogenic

0.79

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over