rs1555063811

Variant names:

• chr11-103191515-A-G
• rs1555063811
• NM_001080463.2:c.7438-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001080463.2(DYNC2H1):​c.7438-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,443,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 9.32
• Publications: 1 publications found

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]

DYNC2H1 Gene-Disease associations (from GenCC):

• asphyxiating thoracic dystrophy 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Majewski type

  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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-103191515-A-G is Pathogenic according to our data. Variant chr11-103191515-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 446535.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.7438-2A>G		splice_acceptor_variant, intron_variant	Intron 45 of 89	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.7438-2A>G		splice_acceptor_variant, intron_variant	Intron 45 of 88	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.7438-2A>G		splice_acceptor_variant, intron_variant	Intron 45 of 89		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.7438-2A>G		splice_acceptor_variant, intron_variant	Intron 45 of 88	1	NM_001377.3	ENSP00000364887.2
DYNC2H1	ENST00000334267.11	c.2205+57096A>G		intron_variant	Intron 15 of 19	1		ENSP00000334021.7
DYNC2H1	ENST00000649323.1	n.*4983-2A>G		splice_acceptor_variant, intron_variant	Intron 43 of 50			ENSP00000497581.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1443494 Hom.: 0 Cov.: 29 AF XY: 0.00000558 AC XY: 4 AN XY: 716466

African (AFR) AF: 0.00 AC: 0 AN: 33282

American (AMR) AF: 0.00 AC: 0 AN: 42680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25730

East Asian (EAS) AF: 0.00 AC: 0 AN: 39220

South Asian (SAS) AF: 0.00 AC: 0 AN: 83434

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000363 AC: 4 AN: 1101242

Other (OTH) AF: 0.00 AC: 0 AN: 59636

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Asphyxiating thoracic dystrophy 3 Pathogenic:2

-

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 01, 2017

Dan Cohn Lab, University Of California Los Angeles

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jeune thoracic dystrophy Pathogenic:1

Sep 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 446535). Disruption of this splice site has been observed in individual(s) with short-rib thoracic dysplasia with polydactyly (PMID: 29068549). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 45 of the DYNC2H1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DYNC2H1 are known to be pathogenic (PMID: 23339108, 32753734, 33755199). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		9.3
GERP RS		5.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.88		Position offset: 2

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

Other links and lift over

dbSNP: rs1555063811; hg19: chr11-103062244;