chr11-68685006-T-C

Variant names:

• chr11-68685006-T-C
• rs1229717084
• NM_015973.5:c.81+2T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_015973.5(GAL):​c.81+2T>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,434,646 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: GAL NM_015973.5 splice_donor, intron
• Scores: Splicing: ADA: 0.9854
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.67
• Publications: 0 publications found

Genes affected

GAL (HGNC:4114): (galanin and GMAP prepropeptide) This gene encodes a neuroendocrine peptide that is widely expressed in the central and peripheral nervous systems and also the gastrointestinal tract, pancreas, adrenal gland and urogenital tract. The encoded protein is a precursor that is proteolytically processed to generate two mature peptides: galanin and galanin message-associated peptide (GMAP). Galanin has diverse physiological functions including nociception, feeding and energy homeostasis, osmotic regulation and water balance. GMAP has been demonstrated to possess antifungal activity and hypothesized to be part of the innate immune system. [provided by RefSeq, Jul 2015]

GAL Gene-Disease associations (from GenCC):

• familial temporal lobe epilepsy 8

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

LOC107984343 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.21774194 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.4, offset of 4, new splice context is: caaGTgcgg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015973.5. 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
	GAL	NM_015973.5	MANE Select	c.81+2T>C		splice_donor intron	N/A	NP_057057.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAL	ENST00000265643.4	TSL:1 MANE Select	c.81+2T>C		splice_donor intron	N/A	ENSP00000265643.3	P22466
	GAL	ENST00000933457.1		c.81+2T>C		splice_donor intron	N/A	ENSP00000603516.1
	GAL	ENST00000933456.1		c.81+2T>C		splice_donor intron	N/A	ENSP00000603515.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 204326 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1434646 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 712514

African (AFR) AF: 0.00 AC: 0 AN: 32892

American (AMR) AF: 0.0000233 AC: 1 AN: 42978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25594

East Asian (EAS) AF: 0.00 AC: 0 AN: 38726

South Asian (SAS) AF: 0.00 AC: 0 AN: 82894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096060

Other (OTH) AF: 0.00 AC: 0 AN: 59306

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Benign	0.96
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Benign	0.46	N
PhyloP100		1.7
GERP RS		3.2
PromoterAI		-0.23	Neutral
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.58
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.84		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1229717084; hg19: chr11-68452474;