rs201479015

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:5
• 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	UniProt
DYNC2H1	NM_001080463.2	c.11747G>A	p.Gly3916Asp	missense_variant, splice_region_variant	82/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.11726G>A	p.Gly3909Asp	missense_variant, splice_region_variant	81/89	ENST00000375735.7

Ensembl

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

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:5

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	- -

Jeune thoracic dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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
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;