NM_001267550.2:c.34307A>G

Variant names:

• chr2-178677272-T-C
• rs568554504
• NM_001267550.2:c.34307A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001267550.2(TTN):​c.34307A>G​(p.Lys11436Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000367 in 1,212,450 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 26)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 4.01
• Publications: 0 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0079436).
• BP6: Variant 2-178677272-T-C is Benign according to our data. Variant chr2-178677272-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 405077.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00175 (258/147368) while in subpopulation AFR AF = 0.0062 (245/39518). AF 95% confidence interval is 0.00556. There are 1 homozygotes in GnomAd4. There are 108 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.

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.34307A>G	p.Lys11436Arg	missense	Exon 147 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.33340+349A>G		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.30559+349A>G		intron	N/A	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.34307A>G	p.Lys11436Arg	missense	Exon 147 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.34307A>G	p.Lys11436Arg	missense	Exon 147 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.34031A>G	p.Lys11344Arg	missense	Exon 145 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 258 AN: 147286 Hom.: 1 Cov.: 26

Gnomad AFR AF: 0.00621

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000621

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00197

GnomAD2 exomes AF: 0.000649 AC: 4 AN: 6164 AF XY: 0.00

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000176 AC: 187 AN: 1065082 Hom.: 0 Cov.: 30 AF XY: 0.000137 AC XY: 69 AN XY: 502860

African (AFR) AF: 0.00758 AC: 168 AN: 22154

American (AMR) AF: 0.000627 AC: 5 AN: 7972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13840

East Asian (EAS) AF: 0.00 AC: 0 AN: 24690

South Asian (SAS) AF: 0.00 AC: 0 AN: 19280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2834

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 911396

Other (OTH) AF: 0.000329 AC: 14 AN: 42576

GnomAD4 genome AF: 0.00175 AC: 258 AN: 147368 Hom.: 1 Cov.: 26 AF XY: 0.00151 AC XY: 108 AN XY: 71752

African (AFR) AF: 0.00620 AC: 245 AN: 39518

American (AMR) AF: 0.000620 AC: 9 AN: 14512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3432

East Asian (EAS) AF: 0.00 AC: 0 AN: 4898

South Asian (SAS) AF: 0.00 AC: 0 AN: 4610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67304

Other (OTH) AF: 0.00195 AC: 4 AN: 2050

Alfa AF: 0.00157 Hom.: 0

Bravo AF: 0.00231

ExAC AF: 0.000871 AC: 4

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Benign	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0079	T
PhyloP100		4.0
Vest4		0.20
MVP		0.67
GERP RS		6.2
Mutation Taster		=17/83	disease causing

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: rs568554504; hg19: chr2-179541999;