chr2-178578869-C-T

Variant names:

• chr2-178578869-C-T
• rs374492812
• NM_001267550.2:c.68161G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001267550.2(TTN):​c.68161G>A​(p.Glu22721Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,613,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E22721E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:3
• Conservation: PhyloP100: 7.86
• Publications: 7 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]

ENSG00000270574 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19576806).
• BP6: Variant 2-178578869-C-T is Benign according to our data. Variant chr2-178578869-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191911.

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.68161G>A	p.Glu22721Lys	missense	Exon 320 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.63238G>A	p.Glu21080Lys	missense	Exon 270 of 313	NP_001243779.1
	TTN	NM_133378.4		c.60457G>A	p.Glu20153Lys	missense	Exon 269 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.68161G>A	p.Glu22721Lys	missense	Exon 320 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.68005G>A	p.Glu22669Lys	missense	Exon 318 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.67885G>A	p.Glu22629Lys	missense	Exon 318 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000117 AC: 29 AN: 248288 AF XY: 0.0000817

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000801

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000102 AC: 149 AN: 1460988 Hom.: 0 Cov.: 33 AF XY: 0.000105 AC XY: 76 AN XY: 726764

African (AFR) AF: 0.0000897 AC: 3 AN: 33430

American (AMR) AF: 0.000246 AC: 11 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39644

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86188

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53390

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5752

European-Non Finnish (NFE) AF: 0.000110 AC: 122 AN: 1111438

Other (OTH) AF: 0.0000829 AC: 5 AN: 60338

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74390

African (AFR) AF: 0.000313 AC: 13 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

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

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67962

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.000245 Hom.: 0

Bravo AF: 0.000144

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000262 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000108 AC: 13

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Benign	0.97
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.49
MVP		0.34
MPC		0.49
ClinPred		0.068	T
GERP RS		5.9
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs374492812; hg19: chr2-179443596; COSMIC: COSV60050715; COSMIC: COSV60050715;