NM_001264.5:c.1516G>A

Variant names:

• chr6-31116099-C-T
• rs140801967
• NM_001264.5:c.1516G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001264.5(CDSN):​c.1516G>A​(p.Val506Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,611,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: CDSN NM_001264.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.899
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042762935).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00025 (38/152204) while in subpopulation AFR AF = 0.00082 (34/41450). AF 95% confidence interval is 0.000603. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001264.5. 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
	CDSN	NM_001264.5	MANE Select	c.1516G>A	p.Val506Met	missense	Exon 2 of 2	NP_001255.4
	PSORS1C1	NM_014068.3	MANE Select	c.-229+1208C>T		intron	N/A	NP_054787.2	Q9UIG5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDSN	ENST00000376288.3	TSL:1 MANE Select	c.1516G>A	p.Val506Met	missense	Exon 2 of 2	ENSP00000365465.2	Q15517
	PSORS1C1	ENST00000259881.10	TSL:1 MANE Select	c.-229+1208C>T		intron	N/A	ENSP00000259881.9	Q9UIG5-1
	PSORS1C1	ENST00000479581.5	TSL:1	n.61+1208C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152204 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000731 AC: 18 AN: 246236 AF XY: 0.0000298

Gnomad AFR exome AF: 0.000989

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1459730 Hom.: 0 Cov.: 58 AF XY: 0.0000110 AC XY: 8 AN XY: 726048

African (AFR) AF: 0.000538 AC: 18 AN: 33466

American (AMR) AF: 0.000112 AC: 5 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111392

Other (OTH) AF: 0.0000829 AC: 5 AN: 60328

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152204 Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 16 AN XY: 74348

African (AFR) AF: 0.000820 AC: 34 AN: 41450

American (AMR) AF: 0.000262 AC: 4 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000146 Hom.: 0

Bravo AF: 0.000355

ESP6500AA AF: 0.000837 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000924 AC: 11

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.90
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.070
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.019	D
Vest4		0.26
MVP		0.19
MPC		0.95
ClinPred		0.14	T
GERP RS		3.1
gMVP		0.38
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs140801967; hg19: chr6-31083876;