rs1555057881

Positions:

• chr11-103179157-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001080463.2(DYNC2H1):​c.6271A>G​(p.Asn2091Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N2091N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 7.50

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.

• PM1: In a region_of_interest AAA 2 (size 223) in uniprot entity DYHC2_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_001080463.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.6271A>G	p.Asn2091Asp	missense_variant	39/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.6271A>G	p.Asn2091Asp	missense_variant	39/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.6271A>G	p.Asn2091Asp	missense_variant	39/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.6271A>G	p.Asn2091Asp	missense_variant	39/89	1	NM_001377.3	P3
DYNC2H1	ENST00000334267.11	c.2205+44738A>G		intron_variant		1
DYNC2H1	ENST00000649323.1	c.*3816A>G		3_prime_UTR_variant, NMD_transcript_variant	37/51

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461060 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726812

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Asphyxiating thoracic dystrophy 3 Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 11, 2022	The DYNC2H1 c.6271A>G; p.Asn2091Asp variant (rs1555057881) is reported in the literature in a patient with short rib-polydactyly syndrome type 3 (SRPS type III) who also carried an additional pathogenic DYNC2H1 variant (Zhang 2018). The p.Asn2091Asp variant is also reported in ClinVar (Variation ID: 446574). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The asparagine at codon 2091 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.773). However, due to limited information, the clinical significance of this variant is uncertain at this time. References: Zhang W et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. PMID: 29068549. -
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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;D;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	1.9	L;L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.8	D;.;.;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0090	D;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;D
Polyphen		0.99	D;D;D;D
Vest4		0.89
MutPred		0.66		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.80
MPC		0.38
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.88
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555057881; hg19: chr11-103049886;