rs1554460624

Variant names:

• chr7-158902397-GT-G
• rs1554460624
• NM_018051.5:c.1162delT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_018051.5(DYNC2I1):​c.1162delT​(p.Cys388ValfsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYNC2I1 NM_018051.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.51
• Publications: 0 publications found

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]

DYNC2I1 Gene-Disease associations (from GenCC):

• short-rib thoracic dysplasia 8 with or without polydactyly

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Verma-Naumoff type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-158902397-GT-G is Pathogenic according to our data. Variant chr7-158902397-GT-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 437277.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018051.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2I1	NM_018051.5	MANE Select	c.1162delT	p.Cys388ValfsTer23	frameshift	Exon 10 of 25	NP_060521.4
	DYNC2I1	NM_001350914.2		c.1024delT	p.Cys342ValfsTer23	frameshift	Exon 10 of 25	NP_001337843.1
	DYNC2I1	NM_001350915.2		c.589delT	p.Cys197ValfsTer23	frameshift	Exon 9 of 24	NP_001337844.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2I1	ENST00000407559.8	TSL:1 MANE Select	c.1162delT	p.Cys388ValfsTer23	frameshift	Exon 10 of 25	ENSP00000384290.3
	DYNC2I1	ENST00000444851.5	TSL:1	n.493delT		non_coding_transcript_exon	Exon 6 of 20	ENSP00000392608.1
	DYNC2I1	ENST00000467220.1	TSL:2	n.273delT		non_coding_transcript_exon	Exon 5 of 20

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Short-rib thoracic dysplasia 8 with or without polydactyly Pathogenic:1

Dec 20, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1554460624; hg19: chr7-158695088;