chr2-178727218-A-T

Variant names:

• chr2-178727218-A-T
• rs28626194
• NM_001267550.2:c.20147T>A

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.20147T>A​(p.Met6716Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00105 in 1,613,246 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M6716I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0058 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (9 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 3.97
• Publications: 2 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]

ENSG00000267784 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.010240138).
• BP6: Variant 2-178727218-A-T is Benign according to our data. Variant chr2-178727218-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46666.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 = 0.00579 (881/152192) while in subpopulation AFR AF = 0.0205 (850/41560). AF 95% confidence interval is 0.0193. There are 7 homozygotes in GnomAd4. There are 417 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.20147T>A	p.Met6716Lys	missense	Exon 69 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.19196T>A	p.Met6399Lys	missense	Exon 67 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.16415T>A	p.Met5472Lys	missense	Exon 66 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.20147T>A	p.Met6716Lys	missense	Exon 69 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.20147T>A	p.Met6716Lys	missense	Exon 69 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.19871T>A	p.Met6624Lys	missense	Exon 67 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00579 AC: 881 AN: 152074 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00134 AC: 334 AN: 248332 AF XY: 0.000958

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.000755

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000561 AC: 820 AN: 1461054 Hom.: 9 Cov.: 31 AF XY: 0.000491 AC XY: 357 AN XY: 726782

African (AFR) AF: 0.0212 AC: 708 AN: 33430

American (AMR) AF: 0.000738 AC: 33 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

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

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5758

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111460

Other (OTH) AF: 0.00106 AC: 64 AN: 60348

GnomAD4 genome AF: 0.00579 AC: 881 AN: 152192 Hom.: 7 Cov.: 33 AF XY: 0.00560 AC XY: 417 AN XY: 74406

African (AFR) AF: 0.0205 AC: 850 AN: 41560

American (AMR) AF: 0.00137 AC: 21 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67970

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000437 Hom.: 0

Bravo AF: 0.00677

ESP6500AA AF: 0.0198 AC: 76

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.00161 AC: 194

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	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
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Benign	0.87
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.45	T
PhyloP100		4.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.49
Sift	Benign	0.28	T
Polyphen		0.79	P
Vest4		0.60
MVP		0.75
MPC		0.26
ClinPred		0.052	T
GERP RS		6.2
Mutation Taster		=46/54	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: rs28626194; hg19: chr2-179591945;