rs145527033

Variant names:

• chr2-178583027-C-T
• rs145527033
• NM_001267550.2:c.65776G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001267550.2(TTN):​c.65776G>A​(p.Val21926Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,609,610 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 7.86
• 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]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008752406).
• BP6: Variant 2-178583027-C-T is Benign according to our data. Variant chr2-178583027-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 202796.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 = 0.000795 (121/152198) while in subpopulation AFR AF = 0.0026 (108/41566). AF 95% confidence interval is 0.0022. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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.65776G>A	p.Val21926Met	missense	Exon 313 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.60853G>A	p.Val20285Met	missense	Exon 263 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.58072G>A	p.Val19358Met	missense	Exon 262 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.65776G>A	p.Val21926Met	missense	Exon 313 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.65620G>A	p.Val21874Met	missense	Exon 311 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.65500G>A	p.Val21834Met	missense	Exon 311 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000796 AC: 121 AN: 152080 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000313 AC: 77 AN: 245946 AF XY: 0.000255

Gnomad AFR exome AF: 0.00287

Gnomad AMR exome AF: 0.000733

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000359

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.000117 AC: 171 AN: 1457412 Hom.: 0 Cov.: 30 AF XY: 0.000112 AC XY: 81 AN XY: 724748

African (AFR) AF: 0.00210 AC: 70 AN: 33364

American (AMR) AF: 0.000675 AC: 30 AN: 44450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26010

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39336

South Asian (SAS) AF: 0.0000584 AC: 5 AN: 85564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.0000469 AC: 52 AN: 1109516

Other (OTH) AF: 0.000216 AC: 13 AN: 60172

GnomAD4 genome AF: 0.000795 AC: 121 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.000820 AC XY: 61 AN XY: 74394

African (AFR) AF: 0.00260 AC: 108 AN: 41566

American (AMR) AF: 0.000589 AC: 9 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000405 Hom.: 0

Bravo AF: 0.000933

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00328 AC: 13

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000323 AC: 39

EpiCase AF: 0.00

EpiControl AF: 0.0000602

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Benign	0.92
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0088	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.38
MVP		0.64
MPC		0.45
ClinPred		0.035	T
GERP RS		5.8
Mutation Taster		=91/9	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: rs145527033; hg19: chr2-179447754; COSMIC: COSV60334628; COSMIC: COSV60334628;