9-128640942-G-T

Variant names:

• chr9-128640942-G-T
• rs12380424
• NM_052844.4:c.187-3C>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_052844.4(DYNC2I2):​c.187-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 1,578,884 control chromosomes in the GnomAD database, including 399 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (33 hom., cov: 31)
  • Exomes 𝑓: 0.021 (366 hom.)
• Consequence: DYNC2I2 NM_052844.4 splice_region, intron
• Scores: Splicing: ADA: 0.9805
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.45
• Publications: 3 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: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
• BP6: Variant 9-128640942-G-T is Benign according to our data. Variant chr9-128640942-G-T is described in ClinVar as Benign. ClinVar VariationId is 474848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0163 (2476/152138) while in subpopulation NFE AF = 0.0247 (1679/67974). AF 95% confidence interval is 0.0237. There are 33 homozygotes in GnomAd4. There are 1215 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2I2	NM_052844.4	c.187-3C>A		splice_region_variant, intron_variant	Intron 1 of 8	ENST00000372715.7	NP_443076.2
DYNC2I2	XM_047424057.1	c.187-3C>A		splice_region_variant, intron_variant	Intron 2 of 9		XP_047280013.1
DYNC2I2	XM_011519179.3	c.187-3C>A		splice_region_variant, intron_variant	Intron 2 of 9		XP_011517481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2I2	ENST00000372715.7	c.187-3C>A		splice_region_variant, intron_variant	Intron 1 of 8	1	NM_052844.4	ENSP00000361800.2
DYNC2I2	ENST00000419989.2	n.142-3C>A		splice_region_variant, intron_variant	Intron 1 of 4	5		ENSP00000415421.1
DYNC2I2	ENST00000451652.5	n.160-3C>A		splice_region_variant, intron_variant	Intron 1 of 3	2
DYNC2I2	ENST00000480613.6	n.142-3C>A		splice_region_variant, intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2476 AN: 152020 Hom.: 33 Cov.: 31

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.00872

Gnomad ASJ AF: 0.00866

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00643

Gnomad FIN AF: 0.0380

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0247

Gnomad OTH AF: 0.00957

GnomAD2 exomes AF: 0.0159 AC: 3496 AN: 220052 AF XY: 0.0161

Gnomad AFR exome AF: 0.00336

Gnomad AMR exome AF: 0.00589

Gnomad ASJ exome AF: 0.00999

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0339

Gnomad NFE exome AF: 0.0231

Gnomad OTH exome AF: 0.0184

GnomAD4 exome AF: 0.0212 AC: 30220 AN: 1426746 Hom.: 366 Cov.: 34 AF XY: 0.0208 AC XY: 14673 AN XY: 705598

African (AFR) AF: 0.00386 AC: 127 AN: 32880

American (AMR) AF: 0.00548 AC: 229 AN: 41816

Ashkenazi Jewish (ASJ) AF: 0.00983 AC: 233 AN: 23704

East Asian (EAS) AF: 0.0000508 AC: 2 AN: 39342

South Asian (SAS) AF: 0.00634 AC: 517 AN: 81508

European-Finnish (FIN) AF: 0.0333 AC: 1703 AN: 51152

Middle Eastern (MID) AF: 0.00339 AC: 18 AN: 5304

European-Non Finnish (NFE) AF: 0.0241 AC: 26287 AN: 1092170

Other (OTH) AF: 0.0188 AC: 1104 AN: 58870

GnomAD4 genome AF: 0.0163 AC: 2476 AN: 152138 Hom.: 33 Cov.: 31 AF XY: 0.0163 AC XY: 1215 AN XY: 74372

African (AFR) AF: 0.00419 AC: 174 AN: 41510

American (AMR) AF: 0.00870 AC: 133 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00866 AC: 30 AN: 3464

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.00644 AC: 31 AN: 4816

European-Finnish (FIN) AF: 0.0380 AC: 403 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0247 AC: 1679 AN: 67974

Other (OTH) AF: 0.00947 AC: 20 AN: 2112

Alfa AF: 0.0199 Hom.: 51

Bravo AF: 0.0130

Asia WGS AF: 0.00375 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DYNC2I2-related disorder Benign:1

Feb 24, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

not provided Benign:1

Oct 02, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Short-rib thoracic dysplasia 11 with or without polydactyly Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	16
DANN	Benign	0.60
PhyloP100		3.4
Mutation Taster		=83/17	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.72
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.62		Position offset: -8

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

Other links and lift over

dbSNP: rs12380424; hg19: chr9-131403221;