chr6-31116174-C-T

Position:

chr6-31116174-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001264.5(CDSN):c.1441G>A(p.Ala481Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,612,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A481S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

CDSN
NM_001264.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 1.38

Variant links:

Genes affected

CDSN (HGNC:1802): (corneodesmosin) This gene encodes a protein found in corneodesmosomes, which localize to human epidermis and other cornified squamous epithelia. The encoded protein undergoes a series of cleavages during corneocyte maturation. This gene is highly polymorphic in human populations, and variation has been associated with skin diseases such as psoriasis, hypotrichosis and peeling skin syndrome. The gene is located in the major histocompatibility complex (MHC) class I region on chromosome 6. [provided by RefSeq, Dec 2014]

CDSN links:

PSORS1C1 (HGNC:17202): (psoriasis susceptibility 1 candidate 1) This gene is one of several genes thought to confer susceptibility to psoriasis and systemic sclerosis, located on chromosome 6 near the major histocompatibility complex (MHC) class I region. [provided by RefSeq, Sep 2011]

PSORS1C1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029701531).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDSN	NM_001264.5 linkuse as main transcript	c.1441G>A	p.Ala481Thr	missense_variant	2/2	ENST00000376288.3
PSORS1C1	NM_014068.3 linkuse as main transcript	c.-229+1283C>T		intron_variant		ENST00000259881.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDSN	ENST00000376288.3 linkuse as main transcript	c.1441G>A	p.Ala481Thr	missense_variant	2/2	1	NM_001264.5	P1
PSORS1C1	ENST00000259881.10 linkuse as main transcript	c.-229+1283C>T		intron_variant		1	NM_014068.3	P2	Q9UIG5-1

Frequencies

GnomAD3 genomes

AF:

0.000211

AC:

AN:

151992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000629

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000809

AC:

AN:

247144

Hom.:

AF XY:

0.0000745

AC XY:

AN XY:

134302

show subpopulations

Gnomad AFR exome

AF:

0.000260

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00102

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000180

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000466

AC:

AN:

1460074

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

726090

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000576

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000210

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.000627

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000713

Hom.:

Bravo

AF:

0.000200

ESP6500AA

AF:

0.000478

AC:

ESP6500EA

AF:

0.000243

AC:

ExAC

AF:

0.0000747

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2022

The c.1441G>A (p.A481T) alteration is located in exon 2 (coding exon 2) of the CDSN gene. This alteration results from a G to A substitution at nucleotide position 1441, causing the alanine (A) at amino acid position 481 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

CDSN-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 2024

The CDSN c.1441G>A variant is predicted to result in the amino acid substitution p.Ala481Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.097

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.69

M_CAP

Benign

0.017

MetaRNN

Benign

0.030

MetaSVM

Benign

-0.93

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.3

REVEL

Benign

0.035

Sift

Benign

0.12

Sift4G

Benign

0.12

Vest4

0.16

MVP

0.22

MPC

0.95

ClinPred

0.039

GERP RS

3.2

gMVP

0.14

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