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). Synonymous variant affecting the same amino acid position (i.e. T65T) 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, 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	UniProt
DYNC2H1	NM_001080463.2	c.193A>C	p.Thr65Pro	missense_variant, splice_region_variant	1/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.193A>C	p.Thr65Pro	missense_variant, splice_region_variant	1/89	ENST00000375735.7

Ensembl

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