chr11-103455180-C-T

Variant names:

• chr11-103455180-C-T
• rs11225812
• NM_001080463.2:c.12478-6C>T

Variant summary

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

The NM_001080463.2(DYNC2H1):​c.12478-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0879 in 1,608,958 control chromosomes in the GnomAD database, including 6,590 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 0.069 (424 hom., cov: 33)
  • Exomes 𝑓: 0.090 (6166 hom.)
• Consequence: DYNC2H1 NM_001080463.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002026
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.628
• Publications: 7 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), G2P, Orphanet, Ambry Genetics
• 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=-0.86).
• BP6: Variant 11-103455180-C-T is Benign according to our data. Variant chr11-103455180-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 302124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0914 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080463.2. 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.12478-6C>T		splice_region intron	N/A	NP_001073932.1
	DYNC2H1	NM_001377.3	MANE Select	c.12457-6C>T		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.12478-6C>T		splice_region intron	N/A	ENSP00000497174.1
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.12457-6C>T		splice_region intron	N/A	ENSP00000364887.2
	DYNC2H1	ENST00000334267.11	TSL:1	c.2296-6C>T		splice_region intron	N/A	ENSP00000334021.7

Frequencies

GnomAD3 genomes AF: 0.0686 AC: 10435 AN: 152046 Hom.: 421 Cov.: 33

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.0700

Gnomad ASJ AF: 0.0720

Gnomad EAS AF: 0.0591

Gnomad SAS AF: 0.0634

Gnomad FIN AF: 0.0988

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0933

Gnomad OTH AF: 0.0876

GnomAD2 exomes AF: 0.0769 AC: 19086 AN: 248072 AF XY: 0.0787

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.0535

Gnomad ASJ exome AF: 0.0774

Gnomad EAS exome AF: 0.0602

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.0938

Gnomad OTH exome AF: 0.0925

GnomAD4 exome AF: 0.0899 AC: 130931 AN: 1456794 Hom.: 6166 Cov.: 29 AF XY: 0.0891 AC XY: 64555 AN XY: 724852

African (AFR) AF: 0.0140 AC: 468 AN: 33348

American (AMR) AF: 0.0564 AC: 2519 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.0773 AC: 2015 AN: 26054

East Asian (EAS) AF: 0.0715 AC: 2834 AN: 39610

South Asian (SAS) AF: 0.0610 AC: 5247 AN: 86030

European-Finnish (FIN) AF: 0.108 AC: 5742 AN: 53304

Middle Eastern (MID) AF: 0.0703 AC: 405 AN: 5762

European-Non Finnish (NFE) AF: 0.0964 AC: 106785 AN: 1107884

Other (OTH) AF: 0.0817 AC: 4916 AN: 60170

GnomAD4 genome AF: 0.0686 AC: 10440 AN: 152164 Hom.: 424 Cov.: 33 AF XY: 0.0697 AC XY: 5188 AN XY: 74384

African (AFR) AF: 0.0171 AC: 710 AN: 41552

American (AMR) AF: 0.0699 AC: 1068 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0720 AC: 250 AN: 3470

East Asian (EAS) AF: 0.0593 AC: 307 AN: 5180

South Asian (SAS) AF: 0.0647 AC: 312 AN: 4822

European-Finnish (FIN) AF: 0.0988 AC: 1047 AN: 10600

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0933 AC: 6338 AN: 67942

Other (OTH) AF: 0.0866 AC: 183 AN: 2112

Alfa AF: 0.0790 Hom.: 844

Bravo AF: 0.0654

Asia WGS AF: 0.0450 AC: 158 AN: 3476

EpiCase AF: 0.0917

EpiControl AF: 0.0939

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Asphyxiating thoracic dystrophy 3 (2)
-	-	2	Jeune thoracic dystrophy (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.27
DANN	Benign	0.33
PhyloP100		-0.63
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
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: rs11225812; hg19: chr11-103325908; COSMIC: COSV104398127;