rs555339053

Positions:

• chr11-103109767-A-C
• chr11-103109767-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001080463.2(DYNC2H1):​c.193A>C​(p.Thr65Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense, splice_region
• Scores: Splicing: ADA: 0.00005059
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.481

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-103109767-A-C is Pathogenic according to our data. Variant chr11-103109767-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446598.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14947918). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.193A>C	p.Thr65Pro	missense_variant, splice_region_variant	1/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.193A>C	p.Thr65Pro	missense_variant, splice_region_variant	1/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.193A>C	p.Thr65Pro	missense_variant, splice_region_variant	1/90		NM_001080463.2	ENSP00000497174	A1
DYNC2H1	ENST00000375735.7	c.193A>C	p.Thr65Pro	missense_variant, splice_region_variant	1/89	1	NM_001377.3	ENSP00000364887	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460502 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726434

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000316 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Asphyxiating thoracic dystrophy 3 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	Benign	0.25
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.078	.;T;.;T;.;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.69	T;.;T;T;.;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	.;L;L;L;L;L
MutationTaster	Benign	0.91	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.4	.;N;N;.;.;N
REVEL	Benign	0.14
Sift	Benign	0.21	.;T;T;.;.;T
Sift4G	Benign	0.28	.;T;T;.;.;T
Polyphen		0.013, 0.045, 0.0080	.;B;B;B;B;B
Vest4		0.24, 0.23, 0.28
MutPred		0.37		Loss of phosphorylation at T65 (P = 0.0624);Loss of phosphorylation at T65 (P = 0.0624);Loss of phosphorylation at T65 (P = 0.0624);Loss of phosphorylation at T65 (P = 0.0624);Loss of phosphorylation at T65 (P = 0.0624);Loss of phosphorylation at T65 (P = 0.0624);
MVP		0.30
MPC		0.089
ClinPred		0.25	T
GERP RS		0.83
Varity_R		0.47
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000051
dbscSNV1_RF	Benign	0.0020
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: rs555339053; hg19: chr11-102980496;