7-74219990-C-T

Variant names:

• chr7-74219990-C-T
• rs369645558
• NM_032464.3:c.209C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_032464.3(LAT2):​c.209C>T​(p.Ala70Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,613,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. A70E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: LAT2 NM_032464.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.19
• Publications: 2 publications found

Genes affected

LAT2 (HGNC:12749): (linker for activation of T cells family member 2) This gene is one of the contiguous genes at 7q11.23 commonly deleted in Williams syndrome, a multisystem developmental disorder. This gene consists of at least 14 exons, and its alternative splicing generates 3 transcript variants, all encoding the same protein. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027826875).
• BP6: Variant 7-74219990-C-T is Benign according to our data. Variant chr7-74219990-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2267814.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032464.3. 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
	LAT2	NM_032464.3	MANE Select	c.209C>T	p.Ala70Val	missense	Exon 6 of 14	NP_115853.2	Q9GZY6-1
	LAT2	NM_014146.4		c.209C>T	p.Ala70Val	missense	Exon 5 of 13	NP_054865.2
	LAT2	NM_032463.3		c.209C>T	p.Ala70Val	missense	Exon 6 of 14	NP_115852.1	Q9GZY6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAT2	ENST00000460943.6	TSL:1 MANE Select	c.209C>T	p.Ala70Val	missense	Exon 6 of 14	ENSP00000420494.1	Q9GZY6-1
	LAT2	ENST00000275635.11	TSL:1	c.209C>T	p.Ala70Val	missense	Exon 6 of 14	ENSP00000275635.7	Q9GZY6-1
	LAT2	ENST00000344995.9	TSL:1	c.209C>T	p.Ala70Val	missense	Exon 5 of 13	ENSP00000344881.5	Q9GZY6-1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000523 AC: 13 AN: 248502 AF XY: 0.0000666

Gnomad AFR exome AF: 0.0000650

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: 0.000107

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000445 AC: 65 AN: 1461372 Hom.: 0 Cov.: 33 AF XY: 0.0000495 AC XY: 36 AN XY: 727010

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.0000531 AC: 59 AN: 1111962

Other (OTH) AF: 0.0000663 AC: 4 AN: 60376

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74342

African (AFR) AF: 0.0000241 AC: 1 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000654 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000414 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.0080
DANN	Benign	0.62
DEOGEN2	Benign	0.38	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0068	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-3.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.021
Sift	Benign	0.22	T
Sift4G	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.061
MutPred		0.14		Loss of disorder (P = 0.0662)
MVP		0.055
MPC		0.087
ClinPred		0.048	T
GERP RS		-6.3
Varity_R		0.028
gMVP		0.059
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs369645558; hg19: chr7-73634320; COSMIC: COSV99305700; COSMIC: COSV99305700;