NM_024421.2:c.2292G>T

Variant names:

• chr18-31131789-C-A
• rs148875640
• NM_024421.2:c.2292G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024421.2(DSC1):​c.2292G>T​(p.Met764Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSC1 NM_024421.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.444
• Publications: 0 publications found

Genes affected

DSC1 (HGNC:3035): (desmocollin 1) The protein encoded by this gene is a calcium-dependent glycoprotein that is a member of the desmocollin subfamily of the cadherin superfamily. These desmosomal family members, along with the desmogleins, are found primarily in epithelial cells where they constitute the adhesive proteins of the desmosome cell-cell junction and are required for cell adhesion and desmosome formation. A subtype of IgA pemphigus, a life-threatening autoimmune disease, is characterized by the presence of autoantibodies that target the encoded protein. The desmosomal family members are arranged in two clusters on chromosome 18. Alternative splicing of this gene results in multiple transcript variants. At least one of these variants encodes a preproprotein that is proteolytically processed to generate the mature protein. [provided by RefSeq, Nov 2015]

DSCAS (HGNC:51116): (DSC1/DSC2 antisense RNA)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053244323).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024421.2. 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
	DSC1	NM_024421.2	MANE Select	c.2292G>T	p.Met764Ile	missense	Exon 15 of 16	NP_077739.1	Q08554-1
	DSC1	NM_004948.3		c.2292G>T	p.Met764Ile	missense	Exon 15 of 17	NP_004939.1	Q08554-2
	DSCAS	NR_110785.1		n.209-19010C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSC1	ENST00000257198.6	TSL:2 MANE Select	c.2292G>T	p.Met764Ile	missense	Exon 15 of 16	ENSP00000257198.6	Q08554-1
	DSC1	ENST00000257197.7	TSL:1	c.2292G>T	p.Met764Ile	missense	Exon 15 of 17	ENSP00000257197.3	Q08554-2
	DSCAS	ENST00000654403.3		n.1484C>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.44
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.13
Sift	Benign	0.41	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.44		Loss of disorder (P = 0.06)
MVP		0.35
MPC		0.068
ClinPred		0.083	T
GERP RS		-1.4
Varity_R		0.13
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs148875640; hg19: chr18-28711752;