9-128640942-G-T

Position:

• chr9-128640942-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. 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

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 9-128640942-G-T is Benign according to our data. Variant chr9-128640942-G-T is described in ClinVar as [Benign]. Clinvar id is 474848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128640942-G-T is described in Lovd as [Likely_benign]. Variant chr9-128640942-G-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2I2	NM_052844.4	c.187-3C>A		splice_region_variant, intron_variant		ENST00000372715.7	NP_443076.2
DYNC2I2	XM_047424057.1	c.187-3C>A		splice_region_variant, intron_variant			XP_047280013.1
DYNC2I2	XM_011519179.3	c.187-3C>A		splice_region_variant, intron_variant			XP_011517481.1

Ensembl

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

GnomAD3 exomes AF: 0.0159 AC: 3496 AN: 220052 Hom.: 41 AF XY: 0.0161 AC XY: 1916 AN XY: 118866

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 SAS exome AF: 0.00588

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

Gnomad4 AFR exome AF: 0.00386

Gnomad4 AMR exome AF: 0.00548

Gnomad4 ASJ exome AF: 0.00983

Gnomad4 EAS exome AF: 0.0000508

Gnomad4 SAS exome AF: 0.00634

Gnomad4 FIN exome AF: 0.0333

Gnomad4 NFE exome AF: 0.0241

Gnomad4 OTH exome AF: 0.0188

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

Gnomad4 AFR AF: 0.00419

Gnomad4 AMR AF: 0.00870

Gnomad4 ASJ AF: 0.00866

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00644

Gnomad4 FIN AF: 0.0380

Gnomad4 NFE AF: 0.0247

Gnomad4 OTH AF: 0.00947

Alfa AF: 0.0137 Hom.: 16

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

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 24, 2020

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 02, 2019

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 03, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	16
DANN	Benign	0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs12380424; hg19: chr9-131403221;