rs146569005

chr11-103189698-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001080463.2(DYNC2H1):c.7319C>T(p.Thr2440Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000732 in 1,612,696 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T2440T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (7 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.99

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010034293).
• BP6: Variant 11-103189698-C-T is Benign according to our data. Variant chr11-103189698-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.7319C>T	p.Thr2440Met	missense_variant	45/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.7319C>T	p.Thr2440Met	missense_variant	45/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.7319C>T	p.Thr2440Met	missense_variant	45/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.7319C>T	p.Thr2440Met	missense_variant	45/89	1	NM_001377.3	P3
DYNC2H1	ENST00000334267.11	c.2205+55279C>T		intron_variant		1
DYNC2H1	ENST00000649323.1	c.*4864C>T		3_prime_UTR_variant, NMD_transcript_variant	43/51

Frequencies

GnomAD3 genomes AF: 0.00396 AC: 602 AN: 152000 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00103 AC: 255 AN: 248040 Hom.: 2 AF XY: 0.000780 AC XY: 105 AN XY: 134564

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.000465

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000801

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000394 AC: 576 AN: 1460578 Hom.: 7 Cov.: 31 AF XY: 0.000361 AC XY: 262 AN XY: 726562

Gnomad4 AFR exome AF: 0.0141

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000940

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.000696

GnomAD4 genome AF: 0.00397 AC: 604 AN: 152118 Hom.: 2 Cov.: 32 AF XY: 0.00386 AC XY: 287 AN XY: 74356

Gnomad4 AFR AF: 0.0139

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000400 Hom.: 1

Bravo AF: 0.00459

ESP6500AA AF: 0.0145 AC: 52

ESP6500EA AF: 0.000246 AC: 2

ExAC AF: 0.00145 AC: 175

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.000238

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 10, 2017	- -

Jeune thoracic dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Asphyxiating thoracic dystrophy 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 08, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.2	L;L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.9	N;.;.;N
REVEL	Benign	0.12
Sift	Benign	0.033	D;.;.;D
Sift4G	Benign	0.091	T;.;.;T
Polyphen		0.99	D;D;D;D
Vest4		0.52
MVP		0.55
MPC		0.21
ClinPred		0.017	T
GERP RS		5.5
Varity_R		0.16
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs146569005; hg19: chr11-103060427;