rs1555068270

Variant names:

• chr11-103203777-G-A
• rs1555068270
• NM_001080463.2:c.8311+1G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001080463.2(DYNC2H1):​c.8311+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000492 in 1,423,612 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: 0.0000049 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 9.61
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.008806489 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.3, offset of 36, new splice context is: ctgGTttgt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-103203777-G-A is Pathogenic according to our data. Variant chr11-103203777-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 446592.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.8311+1G>A		splice_donor_variant, intron_variant	Intron 51 of 89	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.8311+1G>A		splice_donor_variant, intron_variant	Intron 51 of 88	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.8311+1G>A		splice_donor_variant, intron_variant	Intron 51 of 89		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.8311+1G>A		splice_donor_variant, intron_variant	Intron 51 of 88	1	NM_001377.3	ENSP00000364887.2
DYNC2H1	ENST00000334267.11	c.2205+69358G>A		intron_variant	Intron 15 of 19	1		ENSP00000334021.7
DYNC2H1	ENST00000649323.1	n.*5835+1G>A		splice_donor_variant, intron_variant	Intron 49 of 50			ENSP00000497581.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000492 AC: 7 AN: 1423612 Hom.: 0 Cov.: 25 AF XY: 0.00000705 AC XY: 5 AN XY: 709328

African (AFR) AF: 0.00 AC: 0 AN: 32282

American (AMR) AF: 0.00 AC: 0 AN: 42160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25456

East Asian (EAS) AF: 0.00 AC: 0 AN: 39360

South Asian (SAS) AF: 0.00 AC: 0 AN: 82796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.00000645 AC: 7 AN: 1084886

Other (OTH) AF: 0.00 AC: 0 AN: 59032

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Jeune thoracic dystrophy Pathogenic:2

Jun 01, 2017

Dan Cohn Lab, University Of California Los Angeles

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

-

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Asphyxiating thoracic dystrophy 3 Pathogenic:1

Mar 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.6
GERP RS		5.1
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.98		Position offset: 35
DS_DL_spliceai		1.0		Position offset: -1

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

Other links and lift over

dbSNP: rs1555068270; hg19: chr11-103074506;