2-206663037-C-G

Position:

• chr2-206663037-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001093730.1(DYTN):​c.1499G>C​(p.Ser500Thr) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: DYTN NM_001093730.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.57

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]

DYTN (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05873683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYTN	NM_001093730.1	c.1499G>C	p.Ser500Thr	missense_variant	11/12	ENST00000452335.2	NP_001087199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYTN	ENST00000452335.2	c.1499G>C	p.Ser500Thr	missense_variant	11/12	1	NM_001093730.1	ENSP00000396593.2
DYTN	ENST00000674258.1	n.2050G>C		non_coding_transcript_exon_variant	14/15

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

The c.1499G>C (p.S500T) alteration is located in exon 11 (coding exon 11) of the DYTN gene. This alteration results from a G to C substitution at nucleotide position 1499, causing the serine (S) at amino acid position 500 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.33
DANN	Benign	0.65
DEOGEN2	Benign	0.0021	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.0	L
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.020
Sift	Benign	0.51	T
Sift4G	Benign	0.54	T
Polyphen		0.0020	B
Vest4		0.049
MutPred		0.076		Loss of loop (P = 0.0603);
MVP		0.014
MPC		0.026
ClinPred		0.037	T
GERP RS		-6.3
Varity_R		0.059
gMVP		0.087

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-207527761;