rs1555057838

Positions:

• chr11-103179047-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001080463.2(DYNC2H1):​c.6161G>C​(p.Cys2054Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,038 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 Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 8.11

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 Likely_pathogenic. Variant got 7 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, 0.904
• PP5: Variant 11-103179047-G-C is Pathogenic according to our data. Variant chr11-103179047-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446688.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.6161G>C	p.Cys2054Ser	missense_variant	39/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.6161G>C	p.Cys2054Ser	missense_variant	39/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.6161G>C	p.Cys2054Ser	missense_variant	39/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.6161G>C	p.Cys2054Ser	missense_variant	39/89	1	NM_001377.3	P3
DYNC2H1	ENST00000334267.11	c.2205+44628G>C		intron_variant		1
DYNC2H1	ENST00000649323.1	c.*3706G>C		3_prime_UTR_variant, NMD_transcript_variant	37/51

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459038 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725772

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Jeune thoracic dystrophy Pathogenic:2

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

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;D;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	.;D;.;D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.2	M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-9.1	D;.;.;D
REVEL	Uncertain	0.55
Sift	Benign	0.062	T;.;.;T
Sift4G	Benign	0.11	T;.;.;T
Polyphen		1.0	D;D;D;D
Vest4		0.93
MutPred		0.75		Gain of disorder (P = 0.0144);Gain of disorder (P = 0.0144);Gain of disorder (P = 0.0144);Gain of disorder (P = 0.0144);
MVP		0.63
MPC		0.38
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.73
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555057838; hg19: chr11-103049776;