rs201479015

Positions:

• chr11-103321029-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001080463.2(DYNC2H1):​c.11747G>A​(p.Gly3916Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,599,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense, splice_region
• Scores: Splicing: ADA: 0.9988
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:6
• Conservation: PhyloP100: 7.45

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.11747G>A	p.Gly3916Asp	missense_variant, splice_region_variant	82/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.11726G>A	p.Gly3909Asp	missense_variant, splice_region_variant	81/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.11747G>A	p.Gly3916Asp	missense_variant, splice_region_variant	82/90		NM_001080463.2	ENSP00000497174	A1
DYNC2H1	ENST00000375735.7	c.11726G>A	p.Gly3909Asp	missense_variant, splice_region_variant	81/89	1	NM_001377.3	ENSP00000364887	P3
DYNC2H1	ENST00000334267.11	c.2206-114914G>A		intron_variant		1		ENSP00000334021
DYNC2H1	ENST00000528670.5	c.905G>A	p.Gly302Asp	missense_variant, splice_region_variant, NMD_transcript_variant	9/17	5		ENSP00000433451

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 151962 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000211 AC: 50 AN: 237428 Hom.: 0 AF XY: 0.000234 AC XY: 30 AN XY: 128420

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000364

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000259

Gnomad OTH exome AF: 0.000345

GnomAD4 exome AF: 0.000152 AC: 220 AN: 1447636 Hom.: 0 Cov.: 31 AF XY: 0.000156 AC XY: 112 AN XY: 718888

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000489

Gnomad4 ASJ exome AF: 0.0000388

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000171

Gnomad4 OTH exome AF: 0.000100

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74346

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000245 Hom.: 0

Bravo AF: 0.000174

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000246 AC: 2

ExAC AF: 0.000157 AC: 19

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 02, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Dec 16, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2022	Observed with a NEK1 gene variant in a patient with SRP in published literature (Thiel et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21211617, 22795106, 29458881, 22482978, 34426522, 34582081) -

Asphyxiating thoracic dystrophy 3 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 12, 2021	The DYNC2H1 c.11747G>A; p.Gly3916Asp variant (rs201479015) is reported in the literature in an individual who was affected with short-rib polydactyly syndrome; however a second variant was not identified (Thiel 2011). This variant is also reported in ClinVar (Variation ID: 30350) and the general population with an allele frequency of 0.019% (52/268,762 alleles) in the Genome Aggregation Database. The glycine at codon 3916 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.17). Due to limited information, the clinical significance of the p.Gly3916Asp variant is uncertain at this time. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 07, 2011	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 07, 2024

Variant summary: DYNC2H1 c.11747G>A (p.Gly3916Asp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00021 in 237428 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DYNC2H1 causing Short-rib thoracic dysplasia (0.00021 vs 0.0025), allowing no conclusion about variant significance. c.11747G>A has been reported in the literature in at least one heterozygous individuals affected with Short-rib thoracic dysplasia carrying a heterozygous NEK1 variant in trans (e.g. Thiel_2011). This report does not provide unequivocal conclusions about association of the variant with Short-rib thoracic dysplasia. One publication reports experimental evidence evaluating an impact on protein function showing cellular disorganization of cartilage and growth plates by IHC in an affected patient sample, however, does not allow convincing conclusions about the variant effect (e.g. Thiel_2011). The following publication has been ascertained in the context of this evaluation (PMID: 21211617). ClinVar contains an entry for this variant (Variation ID: 30350). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Jeune thoracic dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 09, 2022

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 3916 of the DYNC2H1 protein (p.Gly3916Asp). This variant is present in population databases (rs201479015, gnomAD 0.06%). This missense change has been observed in individual(s) with short-rib polydactyly syndrome (PMID: 21211617). ClinVar contains an entry for this variant (Variation ID: 30350). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.051	T;T;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	.;T;.;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.072	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.94	L;L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.9	N;.;.;N
REVEL	Benign	0.17
Sift	Benign	0.15	T;.;.;T
Sift4G	Benign	0.22	T;.;.;T
Polyphen		0.73	P;P;B;B
Vest4		0.67
MVP		0.50
MPC		0.082
ClinPred		0.063	T
GERP RS		5.6
Varity_R		0.35
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
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: rs201479015; hg19: chr11-103191758;