chr8-22070326-C-G

Variant names:

• chr8-22070326-C-G
• NM_001387751.1:c.596C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001387751.1(DMTN):​c.596C>G​(p.Ala199Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DMTN NM_001387751.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.13
• Publications: 0 publications found

Genes affected

DMTN (HGNC:3382): (dematin actin binding protein) The protein encoded by this gene is an actin binding and bundling protein that plays a structural role in erythrocytes, by stabilizing and attaching the spectrin/actin cytoskeleton to the erythrocyte membrane in a phosphorylation-dependent manner. This protein contains a core domain in the N-terminus, and a headpiece domain in the C-terminus that binds F-actin. When purified from erythrocytes, this protein exists as a trimer composed of two 48 kDa polypeptides and a 52 kDa polypeptide. The different subunits arise from alternative splicing in the 3' coding region, where the headpiece domain is located. Disruption of this gene has been correlated with the autosomal dominant Marie Unna hereditary hypotrichosis disease, while loss of heterozygosity of this gene is thought to play a role in prostate cancer progression. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Nov 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38015938).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387751.1. 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
	DMTN	NM_001387751.1	MANE Select	c.596C>G	p.Ala199Gly	missense	Exon 8 of 16	NP_001374680.1	Q08495-1
	DMTN	NM_001114135.5		c.596C>G	p.Ala199Gly	missense	Exon 8 of 16	NP_001107607.1	Q08495-1
	DMTN	NM_001114136.3		c.596C>G	p.Ala199Gly	missense	Exon 8 of 16	NP_001107608.1	Q08495-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMTN	ENST00000358242.6	TSL:5 MANE Select	c.596C>G	p.Ala199Gly	missense	Exon 8 of 16	ENSP00000350977.3	Q08495-1
	DMTN	ENST00000265800.9	TSL:5	c.596C>G	p.Ala199Gly	missense	Exon 8 of 16	ENSP00000265800.5	Q08495-1
	DMTN	ENST00000432128.6	TSL:5	c.596C>G	p.Ala199Gly	missense	Exon 8 of 16	ENSP00000416111.1	Q08495-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.20
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.054	T
Polyphen		1.0	D
Vest4		0.68
MutPred		0.15		Loss of stability (P = 0.0495)
MVP		0.47
MPC		1.0
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.69
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

hg19: chr8-21927837;