6-31116036-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001264.5(CDSN):c.1579A>G(p.Asn527Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.751 in 1,606,800 control chromosomes in the GnomAD database, including 456,313 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (47124 hom., cov: 31)
  • Exomes 𝑓: 0.75 (409189 hom.)
• Consequence: CDSN NM_001264.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00400

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.6709565E-7).
• BP6: Variant 6-31116036-T-C is Benign according to our data. Variant chr6-31116036-T-C is described in ClinVar as [Benign]. Clinvar id is 1209846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-31116036-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDSN	NM_001264.5	c.1579A>G	p.Asn527Asp	missense_variant	2/2	ENST00000376288.3
PSORS1C1	NM_014068.3	c.-229+1145T>C		intron_variant		ENST00000259881.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDSN	ENST00000376288.3	c.1579A>G	p.Asn527Asp	missense_variant	2/2	1	NM_001264.5	P1
PSORS1C1	ENST00000259881.10	c.-229+1145T>C		intron_variant		1	NM_014068.3	P2

Frequencies

GnomAD3 genomes AF: 0.782 AC: 118757 AN: 151792 Hom.: 47082 Cov.: 31

Gnomad AFR AF: 0.897

Gnomad AMI AF: 0.661

Gnomad AMR AF: 0.754

Gnomad ASJ AF: 0.822

Gnomad EAS AF: 0.883

Gnomad SAS AF: 0.835

Gnomad FIN AF: 0.630

Gnomad MID AF: 0.787

Gnomad NFE AF: 0.731

Gnomad OTH AF: 0.775

GnomAD3 exomes AF: 0.758 AC: 185183 AN: 244312 Hom.: 71279 AF XY: 0.763 AC XY: 101481 AN XY: 133068

Gnomad AFR exome AF: 0.898

Gnomad AMR exome AF: 0.687

Gnomad ASJ exome AF: 0.824

Gnomad EAS exome AF: 0.891

Gnomad SAS exome AF: 0.836

Gnomad FIN exome AF: 0.636

Gnomad NFE exome AF: 0.734

Gnomad OTH exome AF: 0.772

GnomAD4 exome AF: 0.748 AC: 1088003 AN: 1454890 Hom.: 409189 Cov.: 45 AF XY: 0.751 AC XY: 543475 AN XY: 723624

Gnomad4 AFR exome AF: 0.899

Gnomad4 AMR exome AF: 0.698

Gnomad4 ASJ exome AF: 0.820

Gnomad4 EAS exome AF: 0.872

Gnomad4 SAS exome AF: 0.833

Gnomad4 FIN exome AF: 0.639

Gnomad4 NFE exome AF: 0.737

Gnomad4 OTH exome AF: 0.761

GnomAD4 genome AF: 0.782 AC: 118851 AN: 151910 Hom.: 47124 Cov.: 31 AF XY: 0.779 AC XY: 57846 AN XY: 74228

Gnomad4 AFR AF: 0.897

Gnomad4 AMR AF: 0.753

Gnomad4 ASJ AF: 0.822

Gnomad4 EAS AF: 0.883

Gnomad4 SAS AF: 0.836

Gnomad4 FIN AF: 0.630

Gnomad4 NFE AF: 0.731

Gnomad4 OTH AF: 0.772

Alfa AF: 0.752 Hom.: 93223

Bravo AF: 0.796

TwinsUK AF: 0.745 AC: 2761

ALSPAC AF: 0.741 AC: 2854

ESP6500AA AF: 0.899 AC: 3222

ESP6500EA AF: 0.750 AC: 5395

ExAC AF: 0.761 AC: 89564

Asia WGS AF: 0.808 AC: 2810 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Peeling skin syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.4
Dann	Benign	0.75
DEOGEN2	Benign	0.0025	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00073	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	8.7e-7	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.032
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.014
MPC		0.35
ClinPred		0.0034	T
GERP RS		-1.2
gMVP		0.040

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: rs3130981; hg19: chr6-31083813;