rs764926983

Positions:

• chr11-103287559-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001080463.2(DYNC2H1):​c.11070G>A​(p.Pro3690=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,459,004 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 B:1
• Conservation: PhyloP100: 0.0660

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.11070G>A	p.Pro3690=	synonymous_variant	76/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.11049G>A	p.Pro3683=	synonymous_variant	75/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.11070G>A	p.Pro3690=	synonymous_variant	76/90		NM_001080463.2	ENSP00000497174	A1
DYNC2H1	ENST00000375735.7	c.11049G>A	p.Pro3683=	synonymous_variant	75/89	1	NM_001377.3	ENSP00000364887	P3
	ENST00000649070.1	n.690+5457C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 247082 Hom.: 0 AF XY: 0.0000224 AC XY: 3 AN XY: 134030

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000332

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1459004 Hom.: 0 Cov.: 31 AF XY: 0.00000689 AC XY: 5 AN XY: 725618

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Jeune thoracic dystrophy Pathogenic:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	- -
Likely pathogenic, criteria provided, single submitter	research	Rare Disease Group, Clinical Genetics, Karolinska Institutet	May 01, 2018	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 02, 2023

Reported with a partial gene deletion on the opposite allele (in trans) in a patient with skeletal and renal findings, but more specific clinical information was not provided (PMID: 35764379); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 33875766, 35764379) -

Asphyxiating thoracic dystrophy 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Human Genetics, Hannover Medical School

Apr 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	0.32
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.51		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.51		Position offset: -26

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

Publications

LitVar

Other links and lift over

dbSNP: rs764926983; hg19: chr11-103158288;