chr2-178672216-A-G

Variant names:

• chr2-178672216-A-G
• rs199561793
• NM_001267550.2:c.34982T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000589042.5(TTN):​c.34982T>C​(p.Val11661Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,566,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/20 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 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: TTN ENST00000589042.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: -0.608
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09058142).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000589042.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.34982T>C	p.Val11661Ala	missense	Exon 155 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.33860T>C	p.Val11287Ala	missense	Exon 151 of 313	NP_001243779.1
	TTN	NM_133378.4		c.31079T>C	p.Val10360Ala	missense	Exon 150 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.34982T>C	p.Val11661Ala	missense	Exon 155 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.34982T>C	p.Val11661Ala	missense	Exon 155 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.34706T>C	p.Val11569Ala	missense	Exon 153 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000856 AC: 13 AN: 151788 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000898 AC: 16 AN: 178126 AF XY: 0.0000944

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000166 AC: 235 AN: 1414358 Hom.: 0 Cov.: 31 AF XY: 0.000146 AC XY: 102 AN XY: 699840

African (AFR) AF: 0.0000313 AC: 1 AN: 31958

American (AMR) AF: 0.00 AC: 0 AN: 37070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25456

East Asian (EAS) AF: 0.00 AC: 0 AN: 36346

South Asian (SAS) AF: 0.00 AC: 0 AN: 82252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.000205 AC: 223 AN: 1086572

Other (OTH) AF: 0.000188 AC: 11 AN: 58574

GnomAD4 genome AF: 0.0000856 AC: 13 AN: 151788 Hom.: 0 Cov.: 32 AF XY: 0.0000944 AC XY: 7 AN XY: 74116

African (AFR) AF: 0.0000242 AC: 1 AN: 41402

American (AMR) AF: 0.00 AC: 0 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67794

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000202 Hom.: 0

Bravo AF: 0.0000982

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000253 AC: 2

ExAC AF: 0.0000616 AC: 7

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	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
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Benign	0.96
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.61
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.091
Sift	Uncertain	0.019	D
Polyphen		0.0010	B
Vest4		0.19
MVP		0.47
MPC		0.10
ClinPred		0.042	T
GERP RS		2.8
PromoterAI		0.019	Neutral
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: rs199561793; hg19: chr2-179536943;