11-103399879-G-A

Variant names:

• chr11-103399879-G-A
• rs10895417
• NM_001080463.2:c.12387+7G>A

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.12366+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 1,605,638 control chromosomes in the GnomAD database, including 180,693 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20164 hom., cov: 32)
  • Exomes 𝑓: 0.47 (160529 hom.)
• Consequence: DYNC2H1 NM_001377.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002362
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.20
• Publications: 15 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-103399879-G-A is Benign according to our data. Variant chr11-103399879-G-A is described in ClinVar as Benign. ClinVar VariationId is 302120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.61 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.12387+7G>A		splice_region intron	N/A	NP_001073932.1	Q8NCM8-2
	DYNC2H1	NM_001377.3	MANE Select	c.12366+7G>A		splice_region 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.12387+7G>A		splice_region intron	N/A	ENSP00000497174.1	Q8NCM8-2
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.12366+7G>A		splice_region intron	N/A	ENSP00000364887.2	Q8NCM8-1
	DYNC2H1	ENST00000334267.11	TSL:1	c.2206-36064G>A		intron	N/A	ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes AF: 0.511 AC: 77607 AN: 151962 Hom.: 20131 Cov.: 32

Gnomad AFR AF: 0.617

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.529

Gnomad SAS AF: 0.547

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.495

GnomAD2 exomes AF: 0.490 AC: 121112 AN: 247116 AF XY: 0.487

Gnomad AFR exome AF: 0.620

Gnomad AMR exome AF: 0.560

Gnomad ASJ exome AF: 0.450

Gnomad EAS exome AF: 0.535

Gnomad FIN exome AF: 0.417

Gnomad NFE exome AF: 0.445

Gnomad OTH exome AF: 0.471

GnomAD4 exome AF: 0.467 AC: 678353 AN: 1453558 Hom.: 160529 Cov.: 30 AF XY: 0.469 AC XY: 339169 AN XY: 723522

African (AFR) AF: 0.629 AC: 20943 AN: 33274

American (AMR) AF: 0.552 AC: 24604 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 11864 AN: 26052

East Asian (EAS) AF: 0.564 AC: 22332 AN: 39612

South Asian (SAS) AF: 0.554 AC: 47600 AN: 85874

European-Finnish (FIN) AF: 0.414 AC: 22047 AN: 53282

Middle Eastern (MID) AF: 0.552 AC: 3173 AN: 5746

European-Non Finnish (NFE) AF: 0.450 AC: 496879 AN: 1105122

Other (OTH) AF: 0.481 AC: 28911 AN: 60062

GnomAD4 genome AF: 0.511 AC: 77688 AN: 152080 Hom.: 20164 Cov.: 32 AF XY: 0.514 AC XY: 38212 AN XY: 74324

African (AFR) AF: 0.617 AC: 25590 AN: 41488

American (AMR) AF: 0.537 AC: 8198 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1578 AN: 3468

East Asian (EAS) AF: 0.529 AC: 2734 AN: 5168

South Asian (SAS) AF: 0.545 AC: 2631 AN: 4824

European-Finnish (FIN) AF: 0.432 AC: 4564 AN: 10558

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.454 AC: 30833 AN: 67988

Other (OTH) AF: 0.495 AC: 1044 AN: 2110

Alfa AF: 0.469 Hom.: 5575

Bravo AF: 0.518

Asia WGS AF: 0.567 AC: 1973 AN: 3476

EpiCase AF: 0.447

EpiControl AF: 0.441

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Asphyxiating thoracic dystrophy 3 (2)
-	-	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	-0.87
CADD	Benign	0.32
DANN	Benign	0.67
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0040
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: rs10895417; hg19: chr11-103270607; COSMIC: COSV62095911; COSMIC: COSV62095911;