rs1555051720

chr11-103158709-G-GAGTCACAAC

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4 PP5

The NM_001080463.2(DYNC2H1):c.4162_4170dup(p.Val1388_Thr1390dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000218 in 1,374,612 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 inframe_insertion
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:4
• Conservation: PhyloP100: 0.935

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001080463.2.
• PP5: Variant 11-103158709-G-GAGTCACAAC is Pathogenic according to our data. Variant chr11-103158709-G-GAGTCACAAC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446585.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.4162_4170dup	p.Val1388_Thr1390dup	inframe_insertion	27/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.4162_4170dup	p.Val1388_Thr1390dup	inframe_insertion	27/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000375735.7	c.4162_4170dup	p.Val1388_Thr1390dup	inframe_insertion	27/89	1	NM_001377.3	P3
DYNC2H1	ENST00000650373.2	c.4162_4170dup	p.Val1388_Thr1390dup	inframe_insertion	27/90		NM_001080463.2	A1
DYNC2H1	ENST00000334267.11	c.2205+24292_2205+24300dup		intron_variant		1
DYNC2H1	ENST00000649323.1	c.*1707_*1715dup		3_prime_UTR_variant, NMD_transcript_variant	25/51

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000218 AC: 3 AN: 1374612 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 679168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000283

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: no assertion criteria provided

Submissions by phenotype

Jeune thoracic dystrophy Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -

Asphyxiating thoracic dystrophy 3 Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555051720; hg19: chr11-103029438;