rs750689118

chr11-103185031-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_001080463.2(DYNC2H1):c.6613C>T(p.Arg2205Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000995 in 1,608,566 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2205H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.65

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 9 ACMG points.

• PM1: In a helix (size 13) in uniprot entity DYHC2_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_001080463.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-103185032-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86
• PP5: Variant 11-103185031-C-T is Pathogenic according to our data. Variant chr11-103185031-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 528897.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.6613C>T	p.Arg2205Cys	missense_variant	41/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.6613C>T	p.Arg2205Cys	missense_variant	41/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.6613C>T	p.Arg2205Cys	missense_variant	41/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.6613C>T	p.Arg2205Cys	missense_variant	41/89	1	NM_001377.3	P3
DYNC2H1	ENST00000334267.11	c.2205+50612C>T		intron_variant		1
DYNC2H1	ENST00000649323.1	c.*4158C>T		3_prime_UTR_variant, NMD_transcript_variant	39/51

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151766 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000809 AC: 2 AN: 247262 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134188

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000560

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000961 AC: 14 AN: 1456682 Hom.: 0 Cov.: 30 AF XY: 0.00000552 AC XY: 4 AN XY: 724602

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00000451

Gnomad4 OTH exome AF: 0.0000666

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151884 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74232

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.00000828 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Jeune thoracic dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2205 of the DYNC2H1 protein (p.Arg2205Cys). This variant is present in population databases (rs750689118, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with DYNC2H1-related conditions. ClinVar contains an entry for this variant (Variation ID: 528897). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DYNC2H1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg2205 amino acid residue in DYNC2H1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19361615, 29068549). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Nov 30, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D;D;.;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.9	M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-7.0	D;.;.;D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;D
Polyphen		1.0	D;D;D;D
Vest4		0.95
MutPred		0.71		Gain of catalytic residue at L2206 (P = 0.0168);Gain of catalytic residue at L2206 (P = 0.0168);Gain of catalytic residue at L2206 (P = 0.0168);Gain of catalytic residue at L2206 (P = 0.0168);
MVP		0.63
MPC		0.43
ClinPred		0.94	D
GERP RS		3.9
Varity_R		0.56
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: rs750689118; hg19: chr11-103055760;