rs551811137

Variant names:

• chr2-178654277-T-C
• rs551811137
• NM_001267550.2:c.38311A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.38311A>G​(p.Lys12771Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,598,902 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00083 (2 hom., cov: 22)
  • Exomes 𝑓: 0.000091 (9 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.965
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011951089).
• BP6: Variant 2-178654277-T-C is Benign according to our data. Variant chr2-178654277-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 413050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000835 (124/148510) while in subpopulation AFR AF = 0.00255 (104/40756). AF 95% confidence interval is 0.00215. There are 2 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.38311A>G	p.Lys12771Glu	missense	Exon 193 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34523-1736A>G		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31742-1736A>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.38311A>G	p.Lys12771Glu	missense	Exon 193 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.38311A>G	p.Lys12771Glu	missense	Exon 193 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.38035A>G	p.Lys12679Glu	missense	Exon 191 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000836 AC: 124 AN: 148402 Hom.: 2 Cov.: 22

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00107

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000445

Gnomad OTH AF: 0.000966

GnomAD2 exomes AF: 0.000227 AC: 54 AN: 237704 AF XY: 0.000146

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.000304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000276

Gnomad OTH exome AF: 0.000678

GnomAD4 exome AF: 0.0000910 AC: 132 AN: 1450392 Hom.: 9 Cov.: 32 AF XY: 0.0000749 AC XY: 54 AN XY: 721322

African (AFR) AF: 0.00237 AC: 79 AN: 33374

American (AMR) AF: 0.000327 AC: 14 AN: 42846

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 83628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48974

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5566

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1110180

Other (OTH) AF: 0.000283 AC: 17 AN: 60072

GnomAD4 genome AF: 0.000835 AC: 124 AN: 148510 Hom.: 2 Cov.: 22 AF XY: 0.000748 AC XY: 54 AN XY: 72176

African (AFR) AF: 0.00255 AC: 104 AN: 40756

American (AMR) AF: 0.00107 AC: 15 AN: 14010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5064

South Asian (SAS) AF: 0.00 AC: 0 AN: 4234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10262

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

European-Non Finnish (NFE) AF: 0.0000445 AC: 3 AN: 67436

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.000506 Hom.: 0

ExAC AF: 0.000219 AC: 26

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.83
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.00027	T
MetaRNN	Benign	0.012	T
PhyloP100		-0.96
Vest4		0.34
MVP		0.68
GERP RS		-2.1
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs551811137; hg19: chr2-179519004;