rs1554478948

Positions:

• chr7-158930469-G-GGGA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The ENST00000407559.8(DYNC2I1):​c.2503_2505dup​(p.Arg835dup) variant causes a inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYNC2I1 ENST00000407559.8 inframe_insertion
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 6.53

Genes affected

DYNC2I1 (HGNC:21862): (dynein 2 intermediate chain 1) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD) and may facilitate the formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes including cell cycle progression, signal transduction, apoptosis, and gene regulation. The encoded protein contains four WD repeats and may play a role in the formation of cilia. Mutations in this gene have been associated with short-rib polydactyly and Jeune syndromes. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000407559.8. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 7-158930469-G-GGGA is Pathogenic according to our data. Variant chr7-158930469-G-GGGA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446630.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2I1	NM_018051.5	c.2503_2505dup	p.Arg835dup	inframe_insertion	21/25	ENST00000407559.8	NP_060521.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2I1	ENST00000407559.8	c.2503_2505dup	p.Arg835dup	inframe_insertion	21/25	1	NM_018051.5	ENSP00000384290	P1
DYNC2I1	ENST00000444851.5	c.*92_*94dup		3_prime_UTR_variant, NMD_transcript_variant	16/20	1		ENSP00000392608
DYNC2I1	ENST00000467220.1	n.4302_4304dup		non_coding_transcript_exon_variant	16/20	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Asphyxiating thoracic dystrophy 3 Pathogenic:2

Pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554478948; hg19: chr7-158723160;