chr11-103189698-C-T

Variant names:

• chr11-103189698-C-T
• rs146569005
• NM_001080463.2:c.7319C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 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
• Publications: 4 publications found

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]

DYNC2H1 Gene-Disease associations (from GenCC):

• asphyxiating thoracic dystrophy 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Majewski type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Verma-Naumoff type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 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 Benign/Likely_benign. ClinVar VariationId is 445783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00397 (604/152118) while in subpopulation AFR AF = 0.0139 (577/41504). AF 95% confidence interval is 0.013. There are 2 homozygotes in GnomAd4. There are 287 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080463.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	NM_001080463.2	MANE Plus Clinical	c.7319C>T	p.Thr2440Met	missense	Exon 45 of 90	NP_001073932.1
	DYNC2H1	NM_001377.3	MANE Select	c.7319C>T	p.Thr2440Met	missense	Exon 45 of 89	NP_001368.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	ENST00000650373.2	MANE Plus Clinical	c.7319C>T	p.Thr2440Met	missense	Exon 45 of 90	ENSP00000497174.1
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.7319C>T	p.Thr2440Met	missense	Exon 45 of 89	ENSP00000364887.2
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+55279C>T		intron	N/A	ENSP00000334021.7

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

GnomAD2 exomes AF: 0.00103 AC: 255 AN: 248040 AF XY: 0.000780

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 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

African (AFR) AF: 0.0141 AC: 471 AN: 33424

American (AMR) AF: 0.000537 AC: 24 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86188

European-Finnish (FIN) AF: 0.0000940 AC: 5 AN: 53184

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5754

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111334

Other (OTH) AF: 0.000696 AC: 42 AN: 60322

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

African (AFR) AF: 0.0139 AC: 577 AN: 41504

American (AMR) AF: 0.00124 AC: 19 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67980

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00129 Hom.: 8

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

Aug 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 10, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jeune thoracic dystrophy Benign:1

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Asphyxiating thoracic dystrophy 3 Benign:1

Apr 08, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.12
Sift	Benign	0.033	D
Sift4G	Benign	0.091	T
Polyphen		0.99	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
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs146569005; hg19: chr11-103060427;