Genetic Variant CNFN:p.Gly68Ser (chr19-42387387-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032488.4(CNFN):c.202G>A(p.Gly68Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G68C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CNFN
NM_032488.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.39

Publications

0 publications found

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:

LIPE-AS1 (HGNC:48589): (LIPE antisense RNA 1)

LIPE-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24746394).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032488.4. 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
	CNFN	NM_032488.4	MANE Select	c.202G>A	p.Gly68Ser	missense	Exon 3 of 4	NP_115877.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CNFN	ENST00000222032.10	TSL:1 MANE Select	c.202G>A	p.Gly68Ser	missense	Exon 3 of 4	ENSP00000222032.4	Q9BYD5
CNFN	ENST00000597255.1	TSL:1	c.202G>A	p.Gly68Ser	missense	Exon 4 of 5	ENSP00000469590.1	Q9BYD5
LIPE-AS1	ENST00000750186.1		n.166C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1448972

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719960

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33178

American (AMR)

AF:

0.0000232

AC:

AN:

43106

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25894

East Asian (EAS)

AF:

0.00

AC:

AN:

38992

South Asian (SAS)

AF:

0.00

AC:

AN:

84722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4526

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1107340

Other (OTH)

AF:

0.00

AC:

AN:

59722

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.300

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.013

Eigen

Benign

-0.056

Eigen_PC

Benign

0.032

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.70

M_CAP

Benign

0.0085

MetaRNN

Benign

0.25

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.83

PhyloP100

1.4

PrimateAI

Uncertain

0.73

PROVEAN

Benign

1.4

REVEL

Benign

0.089

Sift

Benign

1.0

Sift4G

Benign

0.97

Polyphen

0.82

Vest4

0.43

MutPred

0.48

Gain of glycosylation at G68 (P = 0.0341)

MVP

0.29

MPC

0.39

ClinPred

0.65

GERP RS

4.7

Varity_R

0.14

gMVP

0.60

Mutation Taster

=72/28

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over