rs1554771066

Variant names:

• chr9-128634843-T-C
• rs1554771066
• NM_052844.4:c.1060A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM2 PM5 PP5 BP4

The NM_052844.4(DYNC2I2):​c.1060A>G​(p.Thr354Ala) 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. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T354M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYNC2I2 NM_052844.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 2.33
• Publications: 0 publications found

Genes affected

DYNC2I2 (HGNC:28296): (dynein 2 intermediate chain 2) 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), which may facilitate 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. Defects in this gene are a cause of short-rib thoracic dysplasia 11 with or without polydactyly. [provided by RefSeq, Mar 2014]

DYNC2I2 Gene-Disease associations (from GenCC):

• short-rib thoracic dysplasia 11 with or without polydactyly

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-128634842-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 97038.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 9-128634843-T-C is Pathogenic according to our data. Variant chr9-128634843-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 446623.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26510602). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2I2	NM_052844.4	c.1060A>G	p.Thr354Ala	missense_variant	Exon 7 of 9	ENST00000372715.7	NP_443076.2
DYNC2I2	XM_047424057.1	c.1060A>G	p.Thr354Ala	missense_variant	Exon 8 of 10		XP_047280013.1
DYNC2I2	XM_011519179.3	c.976A>G	p.Thr326Ala	missense_variant	Exon 8 of 10		XP_011517481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2I2	ENST00000372715.7	c.1060A>G	p.Thr354Ala	missense_variant	Exon 7 of 9	1	NM_052844.4	ENSP00000361800.2
DYNC2I2	ENST00000483181.1	n.653A>G		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

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

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Jun 01, 2017

Dan Cohn Lab, University Of California Los Angeles

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.026
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N
Sift	Benign	0.051	T
Sift4G	Benign	0.17	T
Vest4		0.49
ClinPred		0.25	T
GERP RS		4.0
Varity_R		0.15
gMVP		0.56
Mutation Taster		=34/66	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554771066; hg19: chr9-131397122;