rs1554771175

Variant names:

• chr9-128635138-A-G
• rs1554771175
• NM_052844.4:c.935T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_052844.4(DYNC2I2):​c.935T>C​(p.Phe312Ser) variant causes a missense 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 (no stars). Synonymous variant affecting the same amino acid position (i.e. F312F) has been classified as Likely benign.

• 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: 3.09
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-128635138-A-G is Pathogenic according to our data. Variant chr9-128635138-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 446626.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052844.4. 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
	DYNC2I2	NM_052844.4	MANE Select	c.935T>C	p.Phe312Ser	missense	Exon 6 of 9	NP_443076.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2I2	ENST00000372715.7	TSL:1 MANE Select	c.935T>C	p.Phe312Ser	missense	Exon 6 of 9	ENSP00000361800.2
	DYNC2I2	ENST00000483181.1	TSL:2	n.528T>C		non_coding_transcript_exon	Exon 2 of 3
	DYNC2I2	ENST00000419989.2	TSL:5	n.*360T>C		downstream_gene	N/A	ENSP00000415421.1

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

Jeune thoracic dystrophy 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.091
Eigen_PC	Benign	-0.045
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.25
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.19	B
Vest4		0.67
MutPred		0.48		Gain of disorder (P = 0.0206)
MVP		0.59
MPC		0.51
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.59
gMVP		0.76
Mutation Taster		=23/77	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: rs1554771175; hg19: chr9-131397417;