NM_004415.4:c.5441_5442delGCinsAT

Variant names:

• chr6-7582703-GC-AT
• NM_004415.4:c.5441_5442delGCinsAT
• DSP p.Ser1814Asn

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_004415.4(DSP):c.5441_5442delGCinsAT (p.Ser1814Asn) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S1814N: Uncertain_significance (ClinVar VariationId 180333, 2 stars); p.S1814R: Uncertain_significance (ClinVar VariationId 1392061, 1 star); p.S1814= (synonymous): Likely_benign (ClinVar VariationId 2943214, 1 star)

• Frequency: Genomes: not found (cov: 31)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.67
• Publications: 0 publications found

Genes affected

DSP (HGNC:3052): (desmoplakin) This gene encodes a protein that anchors intermediate filaments to desmosomal plaques and forms an obligate component of functional desmosomes. Mutations in this gene are the cause of several cardiomyopathies and keratodermas, including skin fragility-woolly hair syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

DSP Gene-Disease associations (from GenCC):

• arrhythmogenic cardiomyopathy with wooly hair and keratoderma

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• keratosis palmoplantaris striata 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, G2P
• skin fragility-woolly hair-palmoplantar keratoderma syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Genomics England PanelApp, Ambry Genetics, G2P
• arrhythmogenic right ventricular dysplasia 8

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• lethal acantholytic epidermolysis bullosa

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• striate palmoplantar keratoderma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe dermatitis-multiple allergies-metabolic wasting syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• familial hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: G2P
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_004415.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	DSP NM_004415.4	MANE Select	c.5441_5442delGCinsAT p.Ser1814Asn	missense	N/A	Prot: NP_004406.2 UniProt:
	DSP NM_001319034.2		c.4112_4113delGCinsAT p.Ser1371Asn	missense	N/A	Prot: NP_001305963.1 UniProt:
	DSP NM_001008844.3		c.3644_3645delGCinsAT p.Ser1215Asn	missense	N/A	Prot: NP_001008844.1 UniProt:

DSP NM_004415.4

MANE Select

HGVSc / HGVSpc.5441_5442delGCinsATp.Ser1814Asn

Exon rankN/A

missense

Prot: NP_004406.2UniProt: P15924-1

DSP NM_001319034.2

HGVSc / HGVSpc.4112_4113delGCinsATp.Ser1371Asn

Exon rankN/A

missense

Prot: NP_001305963.1UniProt: P15924-3

DSP NM_001008844.3

HGVSc / HGVSpc.3644_3645delGCinsATp.Ser1215Asn

Exon rankN/A

missense

Prot: NP_001008844.1UniProt: P15924-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	DSP ENST00000379802.8	TSL:1MANE Select	c.5441_5442delGCinsAT p.Ser1814Asn	missense	N/A	Prot: ENSP00000369129.3 UniProt:
	DSP ENST00000418664.3	TSL:1	c.3644_3645delGCinsAT p.Ser1215Asn	missense	N/A	Prot: ENSP00000396591.2 UniProt:
	DSP ENST00000713904.1		c.5315_5316delGCinsAT p.Ser1772Asn	missense	N/A	Prot: ENSP00000519203.1 UniProt:

DSP ENST00000379802.8

TSL:1MANE Select

HGVSc / HGVSpc.5441_5442delGCinsATp.Ser1814Asn

Exon rankN/A

missense

Prot: ENSP00000369129.3UniProt: P15924-1

DSP ENST00000418664.3

TSL:1

HGVSc / HGVSpc.3644_3645delGCinsATp.Ser1215Asn

Exon rankN/A

missense

Prot: ENSP00000396591.2UniProt: P15924-2

DSP ENST00000713904.1

HGVSc / HGVSpc.5315_5316delGCinsATp.Ser1772Asn

Exon rankN/A

missense

Prot: ENSP00000519203.1UniProt: A0AAQ5BH40

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	4.7

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr6-7582936;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar