rs79466278

Variant names:

• chr2-178756622-T-G
• rs79466278
• NM_001267550.2:c.10854A>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178756622-T-G
• chr2-178756622-T-C

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.10854A>C​(p.Gln3618His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000601 in 1,613,682 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.90
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068344474).
• BP6: Variant 2-178756622-T-G is Benign according to our data. Variant chr2-178756622-T-G is described in ClinVar as Benign. ClinVar VariationId is 47848.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 = 0.00336 (511/152262) while in subpopulation AFR AF = 0.0113 (470/41544). AF 95% confidence interval is 0.0105. There are 5 homozygotes in GnomAd4. There are 237 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.10854A>C	p.Gln3618His	missense	Exon 46 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_133437.4		c.10341A>C	p.Gln3447His	missense	Exon 44 of 192	NP_597681.4	A0A0A0MRA3
	TTN	NM_001256850.1		c.10303+2362A>C		intron	N/A	NP_001243779.1	Q8WZ42-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.10854A>C	p.Gln3618His	missense	Exon 46 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.10854A>C	p.Gln3618His	missense	Exon 46 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.10578A>C	p.Gln3526His	missense	Exon 44 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 511 AN: 152144 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

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: 0.00

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000776 AC: 193 AN: 248578 AF XY: 0.000526

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.000638

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000314 AC: 459 AN: 1461420 Hom.: 1 Cov.: 33 AF XY: 0.000257 AC XY: 187 AN XY: 726998

African (AFR) AF: 0.0112 AC: 376 AN: 33460

American (AMR) AF: 0.000738 AC: 33 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111724

Other (OTH) AF: 0.000712 AC: 43 AN: 60366

GnomAD4 genome AF: 0.00336 AC: 511 AN: 152262 Hom.: 5 Cov.: 33 AF XY: 0.00318 AC XY: 237 AN XY: 74436

African (AFR) AF: 0.0113 AC: 470 AN: 41544

American (AMR) AF: 0.00236 AC: 36 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

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: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00114 Hom.: 1

Bravo AF: 0.00396

ESP6500AA AF: 0.00963 AC: 37

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000952 AC: 115

Asia WGS AF: 0.00173 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	not provided (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	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
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.90
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.030
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.93	T
PhyloP100		1.9
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.039
Sift	Benign	0.041	D
Vest4		0.19
MutPred		0.21		Loss of loop (P = 0.1258)
MVP		0.55
MPC		0.11
ClinPred		0.019	T
GERP RS		2.5
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: rs79466278; hg19: chr2-179621349;