2-206663383-G-T

Variant names:

• chr2-206663383-G-T
• rs367667719
• NM_001093730.1:c.1153C>A

Variant summary

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

The NM_001093730.1(DYTN):​c.1153C>A​(p.Pro385Thr) 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. 13/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P385S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYTN NM_001093730.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.796
• Publications: 1 publications found

Genes affected

DYTN (HGNC:23279): (dystrotelin) This gene belongs to the dystrophin superfamily, which is characterized by the presence of four EF-hand motifs and a ZZ-domain. It is a likely ortholog of the Drosophila 'discontinuous actin hexagon' gene. It is noteworthy that the coding region of this gene lacks two coding exons that are found in the mouse ortholog. Human transcripts including these two exons are subject to nonsense-mediated transcript decay (NMD). On the other hand, transcripts skipping the two coding exons are expressed at very low levels. While this gene maintains an intact CDS, it may be an evolving pseudogene. However, after a discussion about this gene within the RefSeq group, as well as in the consensus coding sequence (CCDS) collaboration, it was decided to keep it as a protein-coding gene in the RefSeq, Ensembl-GENCODE and the CCDS sets. [provided by RefSeq, Jul 2019]

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=0.13310406).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001093730.1. 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
	DYTN	NM_001093730.1	MANE Select	c.1153C>A	p.Pro385Thr	missense	Exon 11 of 12	NP_001087199.1	A2CJ06

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYTN	ENST00000452335.2	TSL:1 MANE Select	c.1153C>A	p.Pro385Thr	missense	Exon 11 of 12	ENSP00000396593.2	A2CJ06
	DYTN	ENST00000674258.1		n.1704C>A		non_coding_transcript_exon	Exon 14 of 15

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.80
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.10
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.029	D
Polyphen		0.99	D
Vest4		0.14
MutPred		0.12		Gain of phosphorylation at P385 (P = 0.057)
MVP		0.25
MPC		0.20
ClinPred		0.88	D
GERP RS		4.0
Varity_R		0.11
gMVP		0.21
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs367667719; hg19: chr2-207528107;