rs756556129

Positions:

• chr11-103177557-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_001080463.2(DYNC2H1):​c.5876T>A​(p.Ile1959Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,448,462 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense, splice_region
• Scores: Splicing: ADA: 0.7982
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.79

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 6 ACMG points.

• PM1: In a region_of_interest AAA 2 (size 223) in uniprot entity DYHC2_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_001080463.2
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-103177557-T-A is Pathogenic according to our data. Variant chr11-103177557-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446582.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.5876T>A	p.Ile1959Asn	missense_variant, splice_region_variant	38/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.5876T>A	p.Ile1959Asn	missense_variant, splice_region_variant	38/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.5876T>A	p.Ile1959Asn	missense_variant, splice_region_variant	38/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.5876T>A	p.Ile1959Asn	missense_variant, splice_region_variant	38/89	1	NM_001377.3	P3
DYNC2H1	ENST00000334267.11	c.2205+43138T>A		intron_variant		1
DYNC2H1	ENST00000649323.1	c.*3421T>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	36/51

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000846 AC: 2 AN: 236436 Hom.: 0 AF XY: 0.00000779 AC XY: 1 AN XY: 128352

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000117

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: 0.00000207 AC: 3 AN: 1448462 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 720098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000760

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

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

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	-	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 06, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29068549) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D;D;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;.;D
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.60	D;D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.9	L;L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.7	D;.;.;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D;.;.;D
Sift4G	Uncertain	0.0060	D;.;.;D
Polyphen		0.41	B;B;P;P
Vest4		0.88
MutPred		0.69		Gain of disorder (P = 0.0157);Gain of disorder (P = 0.0157);Gain of disorder (P = 0.0157);Gain of disorder (P = 0.0157);
MVP		0.58
MPC		0.34
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.77
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.80
dbscSNV1_RF	Benign	0.54
SpliceAI score (max)		0.060		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: rs756556129; hg19: chr11-103048286;