rs648387

Variant names:

• chr11-103253270-G-T
• rs648387
• NM_001080463.2:c.10064-15G>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.10043-15G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,571,088 control chromosomes in the GnomAD database, including 117,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12447 hom., cov: 31)
  • Exomes 𝑓: 0.38 (105351 hom.)
• Consequence: DYNC2H1 NM_001377.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.97
• Publications: 5 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 (BayesDel_noAF=-0.96).
• BP6: Variant 11-103253270-G-T is Benign according to our data. Variant chr11-103253270-G-T is described in ClinVar as Benign. ClinVar VariationId is 93527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 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.10064-15G>T		intron	N/A	NP_001073932.1	Q8NCM8-2
	DYNC2H1	NM_001377.3	MANE Select	c.10043-15G>T		intron	N/A	NP_001368.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	ENST00000650373.2	MANE Plus Clinical	c.10064-15G>T		intron	N/A	ENSP00000497174.1	Q8NCM8-2
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.10043-15G>T		intron	N/A	ENSP00000364887.2	Q8NCM8-1
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+118851G>T		intron	N/A	ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes AF: 0.401 AC: 60708 AN: 151432 Hom.: 12431 Cov.: 31

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.450

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.394

GnomAD2 exomes AF: 0.362 AC: 84744 AN: 234080 AF XY: 0.365

Gnomad AFR exome AF: 0.471

Gnomad AMR exome AF: 0.229

Gnomad ASJ exome AF: 0.326

Gnomad EAS exome AF: 0.445

Gnomad FIN exome AF: 0.360

Gnomad NFE exome AF: 0.361

Gnomad OTH exome AF: 0.355

GnomAD4 exome AF: 0.381 AC: 540843 AN: 1419540 Hom.: 105351 Cov.: 30 AF XY: 0.383 AC XY: 269602 AN XY: 704420

African (AFR) AF: 0.465 AC: 14863 AN: 31958

American (AMR) AF: 0.238 AC: 10089 AN: 42446

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 8131 AN: 25230

East Asian (EAS) AF: 0.494 AC: 19335 AN: 39176

South Asian (SAS) AF: 0.433 AC: 34748 AN: 80188

European-Finnish (FIN) AF: 0.362 AC: 19007 AN: 52490

Middle Eastern (MID) AF: 0.353 AC: 1976 AN: 5602

European-Non Finnish (NFE) AF: 0.379 AC: 410308 AN: 1083876

Other (OTH) AF: 0.382 AC: 22386 AN: 58574

GnomAD4 genome AF: 0.401 AC: 60755 AN: 151548 Hom.: 12447 Cov.: 31 AF XY: 0.401 AC XY: 29656 AN XY: 74032

African (AFR) AF: 0.471 AC: 19465 AN: 41316

American (AMR) AF: 0.304 AC: 4630 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1125 AN: 3464

East Asian (EAS) AF: 0.449 AC: 2307 AN: 5140

South Asian (SAS) AF: 0.453 AC: 2177 AN: 4806

European-Finnish (FIN) AF: 0.369 AC: 3869 AN: 10474

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

European-Non Finnish (NFE) AF: 0.380 AC: 25768 AN: 67832

Other (OTH) AF: 0.392 AC: 825 AN: 2104

Alfa AF: 0.300 Hom.: 1469

Bravo AF: 0.397

Asia WGS AF: 0.447 AC: 1553 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	1	Asphyxiating thoracic dystrophy 3 (1)
-	-	1	Jeune thoracic dystrophy (1)
-	-	1	not provided (1)
-	-	1	Short rib-polydactyly syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.14
DANN	Benign	0.44
PhyloP100		-3.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs648387; hg19: chr11-103123999; COSMIC: COSV62106412;