rs761765709

chr11-103435986-C-Achr11-103435986-C-Gchr11-103435986-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_001080463.2(DYNC2H1):c.12431C>A(p.Pro4144His) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4144L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.36

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 8 ACMG points.

• PM1: In a helix (size 22) in uniprot entity DYHC2_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) 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 chr11-103435985-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2720393.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.12431C>A	p.Pro4144His	missense_variant	86/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.12410C>A	p.Pro4137His	missense_variant	85/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.12431C>A	p.Pro4144His	missense_variant	86/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.12410C>A	p.Pro4137His	missense_variant	85/89	1	NM_001377.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248572 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134850

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460450 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726518

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.40	T;.;T;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.0	M;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.3	D;N;.;.;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;D;.;.;D;D
Sift4G	Uncertain	0.0060	D;D;.;.;D;D
Polyphen		1.0	D;D;D;D;D;.
Vest4		0.87
MutPred		0.70		Gain of helix (P = 0.0496);.;Gain of helix (P = 0.0496);.;.;.;
MVP		0.56
MPC		0.40
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.65

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: rs761765709; hg19: chr11-103306714;