NM_001080463.2:c.6420T>C

Variant names:

• chr11-103181829-T-C
• rs11225584
• NM_001080463.2:c.6420T>C

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.6420T>C​(p.Asn2140Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,595,920 control chromosomes in the GnomAD database, including 11,614 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1019 hom., cov: 31)
  • Exomes 𝑓: 0.12 (10595 hom.)
• Consequence: DYNC2H1 NM_001080463.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.330
• 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), 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=-0.53).
• BP6: Variant 11-103181829-T-C is Benign according to our data. Variant chr11-103181829-T-C is described in ClinVar as Benign. ClinVar VariationId is 302054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.204 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.6420T>C	p.Asn2140Asn	synonymous	Exon 40 of 90	NP_001073932.1
	DYNC2H1	NM_001377.3	MANE Select	c.6420T>C	p.Asn2140Asn	synonymous	Exon 40 of 89	NP_001368.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	ENST00000650373.2	MANE Plus Clinical	c.6420T>C	p.Asn2140Asn	synonymous	Exon 40 of 90	ENSP00000497174.1
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.6420T>C	p.Asn2140Asn	synonymous	Exon 40 of 89	ENSP00000364887.2
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+47410T>C		intron	N/A	ENSP00000334021.7

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16337 AN: 151578 Hom.: 1016 Cov.: 31

Gnomad AFR AF: 0.0766

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.0829

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.105

GnomAD2 exomes AF: 0.115 AC: 26097 AN: 226062 AF XY: 0.119

Gnomad AFR exome AF: 0.0784

Gnomad AMR exome AF: 0.0542

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.217

Gnomad FIN exome AF: 0.132

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.117 AC: 169540 AN: 1444224 Hom.: 10595 Cov.: 31 AF XY: 0.119 AC XY: 85352 AN XY: 717004

African (AFR) AF: 0.0742 AC: 2452 AN: 33060

American (AMR) AF: 0.0575 AC: 2463 AN: 42842

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 2837 AN: 25750

East Asian (EAS) AF: 0.217 AC: 8481 AN: 39036

South Asian (SAS) AF: 0.160 AC: 13364 AN: 83598

European-Finnish (FIN) AF: 0.133 AC: 6997 AN: 52550

Middle Eastern (MID) AF: 0.0678 AC: 385 AN: 5676

European-Non Finnish (NFE) AF: 0.114 AC: 125616 AN: 1102144

Other (OTH) AF: 0.117 AC: 6945 AN: 59568

GnomAD4 genome AF: 0.108 AC: 16359 AN: 151696 Hom.: 1019 Cov.: 31 AF XY: 0.109 AC XY: 8093 AN XY: 74130

African (AFR) AF: 0.0770 AC: 3196 AN: 41498

American (AMR) AF: 0.0826 AC: 1255 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 379 AN: 3464

East Asian (EAS) AF: 0.214 AC: 1110 AN: 5178

South Asian (SAS) AF: 0.170 AC: 819 AN: 4818

European-Finnish (FIN) AF: 0.134 AC: 1416 AN: 10572

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7742 AN: 67674

Other (OTH) AF: 0.103 AC: 216 AN: 2100

Alfa AF: 0.111 Hom.: 3027

Bravo AF: 0.101

Asia WGS AF: 0.165 AC: 575 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	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	-0.53
CADD	Benign	3.8
DANN	Benign	0.46
PhyloP100		0.33
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: rs11225584; hg19: chr11-103052558; COSMIC: COSV62094382;