6-31116089-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001264.5(CDSN):c.1526T>C(p.Leu509Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000172 in 1,611,972 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L509L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000085 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: CDSN NM_001264.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.89

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]

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016847491).
• BP6: Variant 6-31116089-A-G is Benign according to our data. Variant chr6-31116089-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1551918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000854 (13/152162) while in subpopulation EAS AF= 0.00212 (11/5186). AF 95% confidence interval is 0.00119. There are 1 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDSN	NM_001264.5	c.1526T>C	p.Leu509Pro	missense_variant	2/2	ENST00000376288.3
PSORS1C1	NM_014068.3	c.-229+1198A>G		intron_variant		ENST00000259881.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDSN	ENST00000376288.3	c.1526T>C	p.Leu509Pro	missense_variant	2/2	1	NM_001264.5	P1
PSORS1C1	ENST00000259881.10	c.-229+1198A>G		intron_variant		1	NM_014068.3	P2

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152162 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000544 AC: 134 AN: 246310 Hom.: 0 AF XY: 0.000559 AC XY: 75 AN XY: 134200

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00553

Gnomad SAS exome AF: 0.000923

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000362

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000182 AC: 265 AN: 1459810 Hom.: 1 Cov.: 58 AF XY: 0.000212 AC XY: 154 AN XY: 726110

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00204

Gnomad4 SAS exome AF: 0.00113

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000648

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152162 Hom.: 1 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74318

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.000155

ExAC AF: 0.000547 AC: 65

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CDSN-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 28, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.65
MVP		0.47
MPC		1.3
ClinPred		0.14	T
GERP RS		4.2
gMVP		0.69

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: rs375368228; hg19: chr6-31083866;