rs78309870

chr11-103223093-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001080463.2(DYNC2H1):c.9353+7G>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 0.00538 in 1,593,974 control chromosomes in the GnomAD database, including 332 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (180 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (152 hom.)
• Consequence: DYNC2H1 NM_001080463.2 splice_region, intron
• Scores: Splicing: ADA: 0.00007715
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.362

Genes affected

DYNC2H1 (HGNC:2962): (dynein cytoplasmic 2 heavy chain 1) This gene encodes a large cytoplasmic dynein protein that is involved in retrograde transport in the cilium and has a role in intraflagellar transport, a process required for ciliary/flagellar assembly. Mutations in this gene cause a heterogeneous spectrum of conditions related to altered primary cilium function and often involve polydactyly, abnormal skeletogenesis, and polycystic kidneys. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 11-103223093-G-A is Benign according to our data. Variant chr11-103223093-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 302080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-103223093-G-A is described in Lovd as [Benign]. Variant chr11-103223093-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.9353+7G>A		splice_region_variant, intron_variant		ENST00000650373.2
DYNC2H1	NM_001377.3	c.9353+7G>A		splice_region_variant, intron_variant		ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000375735.7	c.9353+7G>A		splice_region_variant, intron_variant		1	NM_001377.3	P3
DYNC2H1	ENST00000650373.2	c.9353+7G>A		splice_region_variant, intron_variant			NM_001080463.2	A1
DYNC2H1	ENST00000334267.11	c.2205+88674G>A		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.0264 AC: 4010 AN: 152056 Hom.: 180 Cov.: 32

Gnomad AFR AF: 0.0897

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.00748 AC: 1628 AN: 217636 Hom.: 60 AF XY: 0.00571 AC XY: 672 AN XY: 117760

Gnomad AFR exome AF: 0.0932

Gnomad AMR exome AF: 0.00632

Gnomad ASJ exome AF: 0.00585

Gnomad EAS exome AF: 0.00228

Gnomad SAS exome AF: 0.000215

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000799

Gnomad OTH exome AF: 0.00551

GnomAD4 exome AF: 0.00316 AC: 4553 AN: 1441800 Hom.: 152 Cov.: 30 AF XY: 0.00285 AC XY: 2040 AN XY: 715814

Gnomad4 AFR exome AF: 0.0920

Gnomad4 AMR exome AF: 0.00684

Gnomad4 ASJ exome AF: 0.00533

Gnomad4 EAS exome AF: 0.00174

Gnomad4 SAS exome AF: 0.000263

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000468

Gnomad4 OTH exome AF: 0.00765

GnomAD4 genome AF: 0.0264 AC: 4019 AN: 152174 Hom.: 180 Cov.: 32 AF XY: 0.0249 AC XY: 1856 AN XY: 74398

Gnomad4 AFR AF: 0.0897

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000853

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.00821 Hom.: 17

Bravo AF: 0.0303

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Asphyxiating thoracic dystrophy 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

Jeune thoracic dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Short rib-polydactyly syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	6.1
Dann	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000077
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs78309870; hg19: chr11-103093822;