rs3095318

Variant names:

• chr6-31120368-T-A
• rs3095318
• NM_001264.5:c.52A>T

Your query was ambiguous. Multiple possible variants found:

• chr6-31120368-T-A
• chr6-31120368-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001264.5(CDSN):​c.52A>T​(p.Met18Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,592,424 control chromosomes in the GnomAD database, including 40,768 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2244 hom., cov: 30)
  • Exomes 𝑓: 0.22 (38524 hom.)
• Consequence: CDSN NM_001264.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0190
• Publications: 28 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032334626).
• BP6: Variant 6-31120368-T-A is Benign according to our data. Variant chr6-31120368-T-A is described in ClinVar as Benign. ClinVar VariationId is 1244640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

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.52A>T	p.Met18Leu	missense	Exon 1 of 2	NP_001255.4
	PSORS1C1	NM_014068.3	MANE Select	c.-228-5308T>A		intron	N/A	NP_054787.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDSN	ENST00000376288.3	TSL:1 MANE Select	c.52A>T	p.Met18Leu	missense	Exon 1 of 2	ENSP00000365465.2
	PSORS1C1	ENST00000259881.10	TSL:1 MANE Select	c.-228-5308T>A		intron	N/A	ENSP00000259881.9
	PSORS1C1	ENST00000479581.5	TSL:1	n.61+5477T>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24559 AN: 151890 Hom.: 2242 Cov.: 30

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.0960

Gnomad EAS AF: 0.0669

Gnomad SAS AF: 0.0640

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.0764

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.134

GnomAD2 exomes AF: 0.146 AC: 31216 AN: 214444 AF XY: 0.147

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.0691

Gnomad ASJ exome AF: 0.0946

Gnomad EAS exome AF: 0.0971

Gnomad FIN exome AF: 0.123

Gnomad NFE exome AF: 0.212

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.217 AC: 312032 AN: 1440414 Hom.: 38524 Cov.: 41 AF XY: 0.211 AC XY: 151064 AN XY: 714412

African (AFR) AF: 0.132 AC: 4374 AN: 33054

American (AMR) AF: 0.0741 AC: 3095 AN: 41756

Ashkenazi Jewish (ASJ) AF: 0.0982 AC: 2525 AN: 25700

East Asian (EAS) AF: 0.0430 AC: 1661 AN: 38634

South Asian (SAS) AF: 0.0668 AC: 5520 AN: 82602

European-Finnish (FIN) AF: 0.128 AC: 6639 AN: 51762

Middle Eastern (MID) AF: 0.0896 AC: 470 AN: 5244

European-Non Finnish (NFE) AF: 0.250 AC: 275689 AN: 1102144

Other (OTH) AF: 0.203 AC: 12059 AN: 59518

GnomAD4 genome AF: 0.162 AC: 24587 AN: 152010 Hom.: 2244 Cov.: 30 AF XY: 0.153 AC XY: 11365 AN XY: 74278

African (AFR) AF: 0.129 AC: 5337 AN: 41472

American (AMR) AF: 0.103 AC: 1568 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0960 AC: 333 AN: 3468

East Asian (EAS) AF: 0.0670 AC: 346 AN: 5162

South Asian (SAS) AF: 0.0642 AC: 309 AN: 4810

European-Finnish (FIN) AF: 0.124 AC: 1313 AN: 10576

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14829 AN: 67916

Other (OTH) AF: 0.133 AC: 281 AN: 2112

Alfa AF: 0.201 Hom.: 2592

Bravo AF: 0.160

TwinsUK AF: 0.262 AC: 973

ALSPAC AF: 0.280 AC: 1079

ESP6500AA AF: 0.140 AC: 615

ESP6500EA AF: 0.213 AC: 1831

ExAC AF: 0.136 AC: 16375

Asia WGS AF: 0.0700 AC: 246 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.4
DANN	Benign	0.83
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.92	T
PhyloP100		-0.019
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.065
Sift	Benign	0.39	T
Sift4G	Benign	1.0	T
Vest4		0.066
MutPred		0.31		Loss of MoRF binding (P = 0.0694)
MPC		0.29
ClinPred		0.00089	T
GERP RS		0.51
PromoterAI		0.0044	Neutral
gMVP		0.19
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3095318; hg19: chr6-31088145; COSMIC: COSV52548295; COSMIC: COSV52548295;