rs146077746

Variant names:

• chr9-128634895-G-A
• rs146077746
• NM_052844.4:c.1008C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_052844.4(DYNC2I2):​c.1008C>T​(p.Gly336Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,612,834 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: DYNC2I2 NM_052844.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.58
• Publications: 1 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: ClinGen, 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 9-128634895-G-A is Benign according to our data. Variant chr9-128634895-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 474843.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2I2	NM_052844.4	MANE Select	c.1008C>T	p.Gly336Gly	synonymous	Exon 7 of 9	NP_443076.2	Q96EX3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2I2	ENST00000372715.7	TSL:1 MANE Select	c.1008C>T	p.Gly336Gly	synonymous	Exon 7 of 9	ENSP00000361800.2	Q96EX3
	DYNC2I2	ENST00000946364.1		c.1005C>T	p.Gly335Gly	synonymous	Exon 7 of 9	ENSP00000616423.1
	DYNC2I2	ENST00000925011.1		c.990C>T	p.Gly330Gly	synonymous	Exon 7 of 9	ENSP00000595070.1

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152200 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00135 AC: 334 AN: 247386 AF XY: 0.00129

Gnomad AFR exome AF: 0.0000645

Gnomad AMR exome AF: 0.000698

Gnomad ASJ exome AF: 0.00130

Gnomad EAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00450

Gnomad NFE exome AF: 0.00170

Gnomad OTH exome AF: 0.000829

GnomAD4 exome AF: 0.00131 AC: 1907 AN: 1460516 Hom.: 2 Cov.: 33 AF XY: 0.00132 AC XY: 958 AN XY: 726580

African (AFR) AF: 0.000299 AC: 10 AN: 33466

American (AMR) AF: 0.000649 AC: 29 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.000995 AC: 26 AN: 26122

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39688

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86200

European-Finnish (FIN) AF: 0.00389 AC: 205 AN: 52680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5506

European-Non Finnish (NFE) AF: 0.00142 AC: 1576 AN: 1111854

Other (OTH) AF: 0.000829 AC: 50 AN: 60340

GnomAD4 genome AF: 0.00112 AC: 170 AN: 152318 Hom.: 1 Cov.: 33 AF XY: 0.00113 AC XY: 84 AN XY: 74486

African (AFR) AF: 0.000192 AC: 8 AN: 41582

American (AMR) AF: 0.00144 AC: 22 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00367 AC: 39 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00138 AC: 94 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.000740

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00137

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	-	1	Short-rib thoracic dysplasia 11 with or without polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.19
DANN	Benign	0.90
PhyloP100		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.29		Position offset: 6

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

Other links and lift over

dbSNP: rs146077746; hg19: chr9-131397174; COSMIC: COSV100823699; COSMIC: COSV100823699;