rs1555143920

Variant names:

• chr11-103479135-T-C
• rs1555143920
• NM_001080463.2:c.12827T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_001080463.2(DYNC2H1):​c.12827T>C​(p.Leu4276Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 6.63
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001080463.2
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-103479135-T-C is Pathogenic according to our data. Variant chr11-103479135-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 446564.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.12827T>C	p.Leu4276Ser	missense_variant	Exon 90 of 90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.12806T>C	p.Leu4269Ser	missense_variant	Exon 89 of 89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.12827T>C	p.Leu4276Ser	missense_variant	Exon 90 of 90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.12806T>C	p.Leu4269Ser	missense_variant	Exon 89 of 89	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Jeune thoracic dystrophy 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

- -

Asphyxiating thoracic dystrophy 3 Pathogenic:1

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Dec 27, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DYNC2H1 c.12827T>C (p.Leu4276Ser) results in a non-conservative amino acid change located in the Dynein heavy chain C-terminal domain (IPR041228) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249216 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.12827T>C has been reported in the literature in at least one compound heterozygous individual affected with asphyxiating thoracic dystrophy (e.g. Zhang_2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446564). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.;T;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	.;T;T;.;T;T
M_CAP	Uncertain	0.095	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;.;M;.;.;.
PhyloP100		6.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.7	D;N;.;.;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.015	D;D;.;.;D;D
Sift4G	Uncertain	0.035	D;D;.;.;D;D
Polyphen		0.98	D;D;D;D;D;.
Vest4		0.87
MutPred		0.70		Gain of disorder (P = 0.0054);.;Gain of disorder (P = 0.0054);.;.;.;
MVP		0.58
MPC		0.31
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.58
gMVP		0.85
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1555143920; hg19: chr11-103349863;