rs34562585

Variant names:

• chr2-178722825-T-C
• rs34562585
• NM_001267550.2:c.22074A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001267550.2(TTN):​c.22074A>G​(p.Lys7358Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,613,330 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (4 hom., cov: 33)
  • Exomes 𝑓: 0.010 (99 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:28
• Conservation: PhyloP100: 1.99
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 2-178722825-T-C is Benign according to our data. Variant chr2-178722825-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.99 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00637 (970/152226) while in subpopulation NFE AF = 0.0114 (778/67986). AF 95% confidence interval is 0.0108. There are 4 homozygotes in GnomAd4. There are 426 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

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.22074A>G	p.Lys7358Lys	synonymous	Exon 76 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.21123A>G	p.Lys7041Lys	synonymous	Exon 74 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.18342A>G	p.Lys6114Lys	synonymous	Exon 73 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.22074A>G	p.Lys7358Lys	synonymous	Exon 76 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.22074A>G	p.Lys7358Lys	synonymous	Exon 76 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.21798A>G	p.Lys7266Lys	synonymous	Exon 74 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00638 AC: 970 AN: 152108 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00651 AC: 1616 AN: 248350 AF XY: 0.00663

Gnomad AFR exome AF: 0.00278

Gnomad AMR exome AF: 0.00308

Gnomad ASJ exome AF: 0.00388

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00293

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.00483

GnomAD4 exome AF: 0.0104 AC: 15229 AN: 1461104 Hom.: 99 Cov.: 34 AF XY: 0.0102 AC XY: 7419 AN XY: 726798

African (AFR) AF: 0.00215 AC: 72 AN: 33446

American (AMR) AF: 0.00302 AC: 135 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00417 AC: 109 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.000522 AC: 45 AN: 86222

European-Finnish (FIN) AF: 0.00388 AC: 207 AN: 53340

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.0127 AC: 14135 AN: 1111554

Other (OTH) AF: 0.00867 AC: 523 AN: 60310

GnomAD4 genome AF: 0.00637 AC: 970 AN: 152226 Hom.: 4 Cov.: 33 AF XY: 0.00573 AC XY: 426 AN XY: 74406

African (AFR) AF: 0.00243 AC: 101 AN: 41576

American (AMR) AF: 0.00282 AC: 43 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0114 AC: 778 AN: 67986

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00923 Hom.: 0

Bravo AF: 0.00657

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.0102

EpiControl AF: 0.00925

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	6	not provided (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	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.3
DANN	Benign	0.58
PhyloP100		2.0
Mutation Taster		=85/15	polymorphism

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: rs34562585; hg19: chr2-179587552;