19-35507460-T-C

Variant names:

• chr19-35507460-T-C
• rs4254439
• ENST00000419602.5:c.943A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001126056.3(DMKN):​c.943A>G​(p.Arg315Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R315W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: DMKN NM_001126056.3 missense, splice_region
• Scores: Splicing: ADA: 0.001479
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.12
• Publications: 18 publications found

Genes affected

DMKN (HGNC:25063): (dermokine) This gene is upregulated in inflammatory diseases, and it was first observed as expressed in the differentiated layers of skin. The most interesting aspect of this gene is the differential use of promoters and terminators to generate isoforms with unique cellular distributions and domain components. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12562305).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126056.3. 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
	DMKN	NM_033317.5	MANE Select	c.1039-1474A>G		intron	N/A	NP_201574.4
	DMKN	NM_001126056.3		c.943A>G	p.Arg315Gly	missense splice_region	Exon 8 of 18	NP_001119528.3	Q6E0U4-16
	DMKN	NM_001190348.2		c.1126A>G	p.Arg376Gly	missense splice_region	Exon 9 of 13	NP_001177277.1	Q6E0U4-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMKN	ENST00000419602.5	TSL:1	c.943A>G	p.Arg315Gly	missense splice_region	Exon 8 of 18	ENSP00000391036.1	Q6E0U4-16
	DMKN	ENST00000447113.6	TSL:1	c.1126A>G	p.Arg376Gly	missense splice_region	Exon 9 of 13	ENSP00000394908.2	Q6E0U4-6
	DMKN	ENST00000434389.5	TSL:1	c.166A>G	p.Arg56Gly	missense splice_region	Exon 4 of 14	ENSP00000388378.1	H7BZ95

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 156358 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 7.15e-7 AC: 1 AN: 1399032 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 690058

African (AFR) AF: 0.00 AC: 0 AN: 31592

American (AMR) AF: 0.00 AC: 0 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.00 AC: 0 AN: 79222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078712

Other (OTH) AF: 0.00 AC: 0 AN: 57990

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 3247

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.88
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.1
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.037
Sift	Uncertain	0.020	D
Sift4G	Benign	0.42	T
Polyphen		0.0070	B
Vest4		0.14
MutPred		0.15		Loss of stability (P = 0.0838)
MVP		0.20
ClinPred		0.10	T
GERP RS		3.7
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0015
dbscSNV1_RF	Benign	0.068

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

Other links and lift over

dbSNP: rs4254439; hg19: chr19-35998362;