rs78309870

Variant names:

• chr11-103223093-G-A
• rs78309870
• NM_001080463.2:c.9353+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.9353+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 0.00538 in 1,593,974 control chromosomes in the GnomAD database, including 332 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (180 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (152 hom.)
• Consequence: DYNC2H1 NM_001377.3 splice_region, intron
• Scores: Splicing: ADA: 0.00007715
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.362
• Publications: 3 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=-0.8).
• BP6: Variant 11-103223093-G-A is Benign according to our data. Variant chr11-103223093-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 302080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0872 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.9353+7G>A		splice_region intron	N/A	NP_001073932.1	Q8NCM8-2
	DYNC2H1	NM_001377.3	MANE Select	c.9353+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.9353+7G>A		splice_region intron	N/A	ENSP00000497174.1	Q8NCM8-2
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.9353+7G>A		splice_region intron	N/A	ENSP00000364887.2	Q8NCM8-1
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+88674G>A		intron	N/A	ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes AF: 0.0264 AC: 4010 AN: 152056 Hom.: 180 Cov.: 32

Gnomad AFR AF: 0.0897

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.00748 AC: 1628 AN: 217636 AF XY: 0.00571

Gnomad AFR exome AF: 0.0932

Gnomad AMR exome AF: 0.00632

Gnomad ASJ exome AF: 0.00585

Gnomad EAS exome AF: 0.00228

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000799

Gnomad OTH exome AF: 0.00551

GnomAD4 exome AF: 0.00316 AC: 4553 AN: 1441800 Hom.: 152 Cov.: 30 AF XY: 0.00285 AC XY: 2040 AN XY: 715814

African (AFR) AF: 0.0920 AC: 3024 AN: 32860

American (AMR) AF: 0.00684 AC: 287 AN: 41948

Ashkenazi Jewish (ASJ) AF: 0.00533 AC: 137 AN: 25690

East Asian (EAS) AF: 0.00174 AC: 67 AN: 38562

South Asian (SAS) AF: 0.000263 AC: 22 AN: 83646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52362

Middle Eastern (MID) AF: 0.00771 AC: 44 AN: 5708

European-Non Finnish (NFE) AF: 0.000468 AC: 516 AN: 1101446

Other (OTH) AF: 0.00765 AC: 456 AN: 59578

GnomAD4 genome AF: 0.0264 AC: 4019 AN: 152174 Hom.: 180 Cov.: 32 AF XY: 0.0249 AC XY: 1856 AN XY: 74398

African (AFR) AF: 0.0897 AC: 3722 AN: 41516

American (AMR) AF: 0.0107 AC: 164 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3466

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000853 AC: 58 AN: 68010

Other (OTH) AF: 0.0199 AC: 42 AN: 2110

Alfa AF: 0.00973 Hom.: 28

Bravo AF: 0.0303

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Asphyxiating thoracic dystrophy 3 (2)
-	-	2	not provided (2)
-	-	1	Jeune thoracic dystrophy (1)
-	-	1	Short rib-polydactyly syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.1
DANN	Benign	0.52
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000077
dbscSNV1_RF	Benign	0.0
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: rs78309870; hg19: chr11-103093822;