chr2-178535859-A-G

Variant names:

• chr2-178535859-A-G
• rs202214630
• NM_001267550.2:c.100766-10T>C

Variant summary

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

The NM_001267550.2(TTN):​c.100766-10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0731 in 394,778 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (50 hom., cov: 32)
  • Exomes 𝑓: 0.10 (35 hom.)
• Consequence: TTN NM_001267550.2 intron
• Scores: Splicing: ADA: 0.0005632
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.0610
• Publications: 1 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 2-178535859-A-G is Benign according to our data. Variant chr2-178535859-A-G is described in ClinVar as Benign. ClinVar VariationId is 96324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0607 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. 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
	TTN	NM_001267550.2	MANE Select	c.100766-10T>C		intron	N/A	NP_001254479.2
	TTN	NM_001256850.1		c.95843-10T>C		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.93062-10T>C		intron	N/A	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.100766-10T>C		intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.100610-10T>C		intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.100490-10T>C		intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0225 AC: 3237 AN: 143946 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.00453

Gnomad AMI AF: 0.0313

Gnomad AMR AF: 0.0230

Gnomad ASJ AF: 0.0204

Gnomad EAS AF: 0.0663

Gnomad SAS AF: 0.00855

Gnomad FIN AF: 0.0700

Gnomad MID AF: 0.00658

Gnomad NFE AF: 0.0245

Gnomad OTH AF: 0.0208

GnomAD2 exomes AF: 0.0726 AC: 3860 AN: 53194 AF XY: 0.0725

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.0746

Gnomad ASJ exome AF: 0.0442

Gnomad EAS exome AF: 0.139

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.0632

Gnomad OTH exome AF: 0.0645

GnomAD4 exome AF: 0.102 AC: 25620 AN: 250822 Hom.: 35 Cov.: 0 AF XY: 0.101 AC XY: 12423 AN XY: 122542

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0173 AC: 87 AN: 5022

American (AMR) AF: 0.103 AC: 590 AN: 5710

Ashkenazi Jewish (ASJ) AF: 0.0584 AC: 222 AN: 3802

East Asian (EAS) AF: 0.173 AC: 1689 AN: 9768

South Asian (SAS) AF: 0.0395 AC: 389 AN: 9860

European-Finnish (FIN) AF: 0.180 AC: 1955 AN: 10846

Middle Eastern (MID) AF: 0.0360 AC: 42 AN: 1168

European-Non Finnish (NFE) AF: 0.101 AC: 19677 AN: 194544

Other (OTH) AF: 0.0959 AC: 969 AN: 10102

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0225 AC: 3237 AN: 143956 Hom.: 50 Cov.: 32 AF XY: 0.0240 AC XY: 1677 AN XY: 69902

African (AFR) AF: 0.00452 AC: 179 AN: 39586

American (AMR) AF: 0.0230 AC: 330 AN: 14350

Ashkenazi Jewish (ASJ) AF: 0.0204 AC: 67 AN: 3292

East Asian (EAS) AF: 0.0666 AC: 330 AN: 4952

South Asian (SAS) AF: 0.00836 AC: 37 AN: 4426

European-Finnish (FIN) AF: 0.0700 AC: 628 AN: 8976

Middle Eastern (MID) AF: 0.00719 AC: 2 AN: 278

European-Non Finnish (NFE) AF: 0.0245 AC: 1595 AN: 65222

Other (OTH) AF: 0.0207 AC: 41 AN: 1980

Alfa AF: 0.0168 Hom.: 1

Bravo AF: 0.0189

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	17
DANN	Benign	0.90
PhyloP100		0.061
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00056
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.010		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: rs202214630; hg19: chr2-179400586;