rs1214801816

Positions:

• chr11-103199458-C-G
• chr11-103199458-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_001080463.2(DYNC2H1):​c.8070C>G​(p.Phe2690Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,422,198 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 2.15

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 5 ACMG points.

• PM1: In a region_of_interest AAA 4 (size 246) in uniprot entity DYHC2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001080463.2
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-103199458-C-G is Pathogenic according to our data. Variant chr11-103199458-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446603.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.8070C>G	p.Phe2690Leu	missense_variant	49/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.8070C>G	p.Phe2690Leu	missense_variant	49/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.8070C>G	p.Phe2690Leu	missense_variant	49/90		NM_001080463.2	ENSP00000497174	A1
DYNC2H1	ENST00000375735.7	c.8070C>G	p.Phe2690Leu	missense_variant	49/89	1	NM_001377.3	ENSP00000364887	P3
DYNC2H1	ENST00000334267.11	c.2205+65039C>G		intron_variant		1		ENSP00000334021
DYNC2H1	ENST00000649323.1	c.*5594C>G		3_prime_UTR_variant, NMD_transcript_variant	47/51			ENSP00000497581

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1422198 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 704688

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: 9.17e-7

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

Asphyxiating thoracic dystrophy 3 Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;D;.;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	.;T;.;T
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Pathogenic	3.2	M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.8	D;.;.;D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;D
Polyphen		1.0	D;D;D;D
Vest4		0.59
MutPred		0.60		Gain of disorder (P = 0.0868);Gain of disorder (P = 0.0868);Gain of disorder (P = 0.0868);Gain of disorder (P = 0.0868);
MVP		0.66
MPC		0.41
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.93
gMVP		0.83

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: rs1214801816; hg19: chr11-103070187;