rs11225578

Variant names:

• chr11-103173309-A-G
• rs11225578
• NM_001080463.2:c.5558+4A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-103173309-A-G
• chr11-103173309-A-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001377.3(DYNC2H1):​c.5558+4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,522,134 control chromosomes in the GnomAD database, including 11,089 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (848 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10241 hom.)
• Consequence: DYNC2H1 NM_001377.3 splice_region, intron
• Scores: Splicing: ADA: 0.9919
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.70
• Publications: 12 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 11-103173309-A-G is Benign according to our data. Variant chr11-103173309-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 302048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.239 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.5558+4A>G		splice_region intron	N/A	NP_001073932.1	Q8NCM8-2
	DYNC2H1	NM_001377.3	MANE Select	c.5558+4A>G		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.5558+4A>G		splice_region intron	N/A	ENSP00000497174.1	Q8NCM8-2
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.5558+4A>G		splice_region intron	N/A	ENSP00000364887.2	Q8NCM8-1
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+38890A>G		intron	N/A	ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes AF: 0.0950 AC: 14411 AN: 151754 Hom.: 844 Cov.: 32

Gnomad AFR AF: 0.0382

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0815

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.0896

GnomAD2 exomes AF: 0.115 AC: 20486 AN: 177376 AF XY: 0.119

Gnomad AFR exome AF: 0.0349

Gnomad AMR exome AF: 0.0493

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.249

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.117 AC: 160450 AN: 1370262 Hom.: 10241 Cov.: 26 AF XY: 0.118 AC XY: 79995 AN XY: 679518

African (AFR) AF: 0.0322 AC: 912 AN: 28308

American (AMR) AF: 0.0508 AC: 1522 AN: 29978

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 2773 AN: 24012

East Asian (EAS) AF: 0.230 AC: 7858 AN: 34114

South Asian (SAS) AF: 0.142 AC: 9807 AN: 69152

European-Finnish (FIN) AF: 0.115 AC: 5969 AN: 51824

Middle Eastern (MID) AF: 0.123 AC: 656 AN: 5346

European-Non Finnish (NFE) AF: 0.116 AC: 124229 AN: 1070976

Other (OTH) AF: 0.119 AC: 6724 AN: 56552

GnomAD4 genome AF: 0.0950 AC: 14421 AN: 151872 Hom.: 848 Cov.: 32 AF XY: 0.0958 AC XY: 7110 AN XY: 74222

African (AFR) AF: 0.0381 AC: 1581 AN: 41484

American (AMR) AF: 0.0813 AC: 1241 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 395 AN: 3470

East Asian (EAS) AF: 0.251 AC: 1295 AN: 5164

South Asian (SAS) AF: 0.152 AC: 729 AN: 4802

European-Finnish (FIN) AF: 0.111 AC: 1174 AN: 10536

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7676 AN: 67846

Other (OTH) AF: 0.0968 AC: 204 AN: 2108

Alfa AF: 0.110 Hom.: 534

Bravo AF: 0.0890

Asia WGS AF: 0.203 AC: 705 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Jeune thoracic dystrophy (2)
-	-	1	Asphyxiating thoracic dystrophy 3 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	23
DANN	Benign	0.87
PhyloP100		2.7
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.65
SpliceAI score (max)		0.10		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: rs11225578; hg19: chr11-103044038; COSMIC: COSV62101811;