chr11-103287549-C-T

Variant names:

• chr11-103287549-C-T
• rs10895391
• NM_001080463.2:c.11060C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001377.3(DYNC2H1):​c.11039C>T​(p.Ala3680Val) variant causes a missense change. The variant allele was found at a frequency of 0.346 in 1,603,654 control chromosomes in the GnomAD database, including 98,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.30 (7180 hom., cov: 32)
  • Exomes 𝑓: 0.35 (91575 hom.)
• Consequence: DYNC2H1 NM_001377.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 6.03
• Publications: 33 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), Ambry Genetics, Orphanet, G2P, ClinGen
• 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

ENSG00000285878 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032462478).
• BP6: Variant 11-103287549-C-T is Benign according to our data. Variant chr11-103287549-C-T is described in ClinVar as Benign. ClinVar VariationId is 302107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	NM_001080463.2	MANE Plus Clinical	c.11060C>T	p.Ala3687Val	missense	Exon 76 of 90	NP_001073932.1	Q8NCM8-2
	DYNC2H1	NM_001377.3	MANE Select	c.11039C>T	p.Ala3680Val	missense	Exon 75 of 89	NP_001368.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	ENST00000650373.2	MANE Plus Clinical	c.11060C>T	p.Ala3687Val	missense	Exon 76 of 90	ENSP00000497174.1	Q8NCM8-2
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.11039C>T	p.Ala3680Val	missense	Exon 75 of 89	ENSP00000364887.2	Q8NCM8-1
	DYNC2H1	ENST00000334267.11	TSL:1	c.2206-148394C>T		intron	N/A	ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45696 AN: 151842 Hom.: 7174 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.301

GnomAD2 exomes AF: 0.319 AC: 77790 AN: 244088 AF XY: 0.328

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.221

Gnomad ASJ exome AF: 0.283

Gnomad EAS exome AF: 0.279

Gnomad FIN exome AF: 0.334

Gnomad NFE exome AF: 0.352

Gnomad OTH exome AF: 0.325

GnomAD4 exome AF: 0.351 AC: 509918 AN: 1451694 Hom.: 91575 Cov.: 32 AF XY: 0.353 AC XY: 254978 AN XY: 721994

African (AFR) AF: 0.195 AC: 6473 AN: 33268

American (AMR) AF: 0.232 AC: 10218 AN: 44118

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 7643 AN: 25958

East Asian (EAS) AF: 0.290 AC: 11439 AN: 39410

South Asian (SAS) AF: 0.400 AC: 33787 AN: 84372

European-Finnish (FIN) AF: 0.335 AC: 17820 AN: 53190

Middle Eastern (MID) AF: 0.360 AC: 2064 AN: 5732

European-Non Finnish (NFE) AF: 0.362 AC: 399750 AN: 1105670

Other (OTH) AF: 0.346 AC: 20724 AN: 59976

GnomAD4 genome AF: 0.301 AC: 45731 AN: 151960 Hom.: 7180 Cov.: 32 AF XY: 0.302 AC XY: 22429 AN XY: 74282

African (AFR) AF: 0.196 AC: 8139 AN: 41432

American (AMR) AF: 0.271 AC: 4138 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 984 AN: 3464

East Asian (EAS) AF: 0.288 AC: 1489 AN: 5164

South Asian (SAS) AF: 0.389 AC: 1878 AN: 4822

European-Finnish (FIN) AF: 0.351 AC: 3697 AN: 10542

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.357 AC: 24289 AN: 67948

Other (OTH) AF: 0.302 AC: 638 AN: 2112

Alfa AF: 0.334 Hom.: 42319

Bravo AF: 0.285

TwinsUK AF: 0.368 AC: 1364

ALSPAC AF: 0.356 AC: 1371

ESP6500AA AF: 0.204 AC: 742

ESP6500EA AF: 0.352 AC: 2869

ExAC AF: 0.325 AC: 39276

Asia WGS AF: 0.324 AC: 1126 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Asphyxiating thoracic dystrophy 3 (3)
-	-	2	Jeune thoracic dystrophy (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.23
Sift	Benign	0.11	T
Sift4G	Benign	0.12	T
Polyphen		0.60	P
Vest4		0.29
MPC		0.080
ClinPred		0.015	T
GERP RS		5.8
Varity_R		0.49
gMVP		0.50
Mutation Taster		=64/36	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs10895391; hg19: chr11-103158278; COSMIC: COSV62088534;